Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer

Summary

Mitophagy is a selective autophagy that degrades dysfunctional mitochondria to maintain cellular homeostasis. Mitophagy is functionally coordinated with and regulated by mitochondrial biogenesis and mitochondrial dynamics, which include mitochondrial fusion, mitochondrial fission, and mitochondrial trafficking. Furthermore, researches have demonstrated that mitophagy plays a critical role in the occurrence and development of digestive cancer. Nonetheless, the mechanism of how mitophagy modulates digestive cancer and the mechanism of how mitochondrial biogenesis and dynamics influence mitophagy warrant more investigations. This review summarizes the current understanding of the regulatory mechanism of mitophagy and outlines recent advances from investigations that explore how mitochondrial biogenesis and dynamics coordinate with mitophagy. Additionally, this review provides a comprehensive view about how mitophagy could regulate the occurrence and development of digestive cancer. A deeper understanding about the role of mitophagy in regulation of digestive cancer benefits the development of more efficient therapeutic strategies for patients.

Graphical abstract

Biological sciences.

Introduction

Mitochondria are responsible for several important cellular functions such as facilitating oxidative phosphorylation (OXPHOS).^1,2 Dysregulated mitochondrial homeostasis is closely associated with several diseases^3,4,5 (Figure 1). Mitochondrial quality control (MQC) mechanism is crucial to maintain the mitochondrial homeostasis. MQC encompasses several cellular processes, including mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Mitophagy is a selective autophagy that degrades dysfunctional mitochondria to maintain cellular homeostasis. Dysregulation of mitophagy has been linked to several severe diseases, including cancer.⁶

Figure 1.

Overview of mitochondrial function and structure

Mitochondria are organelles surrounded by a double membrane consisting of the outer mitochondrial membrane (OMM), inner mitochondrial membrane (IMM), intermembrane space (IMS), and matrix, which are responsible for several functions such as OXPHOS, regulating cellular metabolism and maintaining Ca²⁺ homeostasis. Dysfunctional mitochondria in various tissues have been linked to a range of pathological conditions, including neurodegenerative disorders, cardiovascular disease, and cancer.

In this review, we explore the regulatory mechanism of mitophagy, the influence of mitochondrial biogenesis and mitochondrial dynamics on mitophagy, and the role of mitophagy in occurrence and development of digestive system cancer. We highlight the current limitations and suggest future issues that need to be addressed.

Molecular mechanism of mitophagy

Mitophagy is primarily achieved through two distinct pathways: the ubiquitin-dependent pathway, which includes the PINK1/Parkin-dependent pathway, and the ubiquitin-independent pathway, which encompasses the receptor-dependent pathway.⁷ Recent studies have further explored the regulatory mechanism of mitophagy.

Regulatory mechanism of mitophagy

In normal condition, PTEN-inducible kinase-1 (PINK1) is cleaved by the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and subsequently degraded by the ubiquitin-proteasome system (UPS).^6,8,9 When mitochondria are depolarized, the PINK1 protein is stabilized in outer mitochondrial membrane (OMM), where it undergoes phosphorylation and recruits the Parkin protein to the OMM. Parkin could ubiquitinate several OMM proteins, including mitofusin 1 (MFN1) and MFN2.¹⁰ The ubiquitinated OMM proteins serve as binding targets for autophagic adaptor proteins, including nuclear dot protein 52 (NDP52), optineurin (OPTN), p62/sequestosome 1 (SQSTM1), and NBR1 (NBR1 autophagy cargo receptor).¹¹ These adaptor proteins are capable of interacting with LC3, which is located on the autophagosome membrane, through its LC3 interactive region (LIR),¹² resulting in degradation of depolarized or dysfunctional mitochondria.

In addition to the ubiquitin-dependent pathway, several OMM proteins could interact with LC3 via their own LIR region to initiate mitophagy, including Nip3-like protein X (NIX)/BCL2-interacting protein 3 like (BNIP3L) receptor, BCL2-interacting protein 3 (BNIP3) receptor, FUN14 domain containing 1 (FUNDC1) receptor, and others.¹³ NIX/BNIP3L is a pro-apoptotic BCL2 family protein that interacts with LC3 to recruit autophagosomes to the target mitochondria. Phosphorylation is a significant post-translational modification of BNIP3L. Phosphorylation of BNIP3L at Serine212 (Ser212) disrupts the dimerization of BNIP3L, thereby attenuating the activity of BNIP3L as a mitophagy receptor. Conversely, phosphorylation at Ser82 is essential for BNIP3L-mediated mitophagy.^14,15 BNIP3, which is homologous to BNIP3L, represents a protein member of the BCL-2 family. Post-translational modification also exerts important role in enhancing the activity of BNIP3 in mitophagy by phosphorylating BNIP3 at Ser17 and Ser24.¹⁶ FUNDC1 is a mitophagy receptor that has recently garnered significant attention. Phosphorylation and ubiquitination are two major post-translational modifications that regulate FUNDC1 activities. Under normal conditions, FUNDC1 is phosphorylated at tyrosine 18 (Tyr18) and Ser13 by Src and CK2 kinase, respectively, or dephosphorylated at Ser17 to maintain its inactivation. Under cellular stress conditions, there are two post-translational modification pathways for FUNDC1 activation. Tyr416-phosphorylated Src kinase promotes FUNDC1 dephosphorylation at Tyr18, and CK2 dissociates from FUNDC1 to enhance FUNDC1 dephosphorylation at Ser13. Unc-51, like autophagy-activating kinase 1 (ULK1), translocates to mitochondria and phosphorylates FUNDC1 at Ser17 to enhance the activity of FUNDC1-mediated mitophagy.¹⁷ Phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial Ser/threonine (Thr) protein phosphatase, is cleaved by PARL, and the PGAM5 truncation product dephosphorylates FUNDC1 at Ser13 to enhance mitophagy. Membrane-associated ring-CH-type finger 5 (MARCH5) directly interacts with FUNDC1 to mediate its ubiquitination at lysine 119 (lys119) for subsequent degradation of FUNDC1. Knockdown of MARCH5 inhibits the degradation of FUNDC1, which could enhance hypoxia-induced mitophagy¹⁸ (Figure 2).

Figure 2.

Regulatory mechanism of mitophagy

In fully polarized mitochondria, PTEN-inducible kinase 1 (PINK1) is imported into the mitochondria via the translocase of the outer membrane (TOM) and the translocase of the inner mitochondrial membrane (TIM). Subsequently, PINK1 is cleaved by the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) on IMM, resulting in the degradation of PINK1 by the ubiquitin-proteasome system (UPS). When mitochondria are depolarized, mitophagy is mainly achieved through the PINK1/Parkin-dependent pathway and the receptor-dependent pathway to degrade the dysfunctional mitochondria.

Recent progress in the regulatory mechanism of mitophagy

Cyclin-dependent kinase (CDK) family is serine/threonine kinase whose activity relies on combination with a regulatory cyclin. There are over 20 members of CDK family with specialized functions, and CDK9 is associated with transcriptional regulation.¹⁹ Yao et al. found that CDK9 inhibition could interrupt the initiation of mitophagy and promote the dysfunction of mitochondria, resulting in cancer cell death. They further demonstrated that CDK9 inhibition could decrease the phosphorylation of SIRT1 and SIRT1-mediated deacetylation of Forkhead box protein O 3 (FOXO3), leading to the degradation of FOXO3 protein and transcriptional suppression of FOXO3-targeted gene BNIP3. Subsequently, the expression of BNIP3 and BNIP3-PINK1 binding decreased, which may cause the decrease of PINK1 stabilization and thus impair PINK1-dependent mitophagy.²⁰ Cai et al. reported that the histone demethylase, KDM4A (lysine demethylase 4A), could upregulate the expression of angiotensinogen (AGT) via H3K9me3 demethylation. The upregulated AGT could coordinate with TRIM21, an E3 ligase, to mediate the ubiquitination of PHB1 and subsequently promote its proteasome-dependent degradation. The decreased PHB1 could interrupt the basal mitophagy, triggering cytoplasmic mitochondrial DNA (mtDNA) accumulation, thereby activating the cGAS-STING signaling pathway and enhancing the secretion of senescence-associated secretory phenotype.²¹ Jin et al. reported that tumor necrosis factor alpha (TNF-α) could exclusively induce the degradation of Myc-interacting zinc-finger protein 1 (Miz1) by E3 ubiquitination. Miz1 degradation could free peroxiredoxin 6 (PRDX6), and the dissociative PRDX6 could be located to membrane of mitochondria (MOM). PRDX6 located to MOM could interact with Parkin at Cys431 site to inhibit Parkin autoubiquitination, thereby suppressing Parkin-dependent mitophagy.²² Activation of acid-sensing ion channel 1a (ASIC1a), a type of cell membrane receptor that is responsive to acidic conditions,²³ has been found to upregulate the expression of calcineurin, which could competitively bind to heat shock protein 70 (HSP70) and disrupt the formation of SIRT3-HSP70 complex, thereby preventing translocation of SIRT3 from cytoplasm to mitochondria. The reduced level of SIRT3 in mitochondria could induce excessive mitophagy in articular chondrocytes, resulting in PANoptosis of chondrocytes.²⁴ OPTN, an autophagic adaptor protein, has been further investigated recently. Wang et al. reported a dual role of OPTN in mitophagy initiation. During the drug-induced liver injury, on the one hand, OPTN could recognize glutaryl-CoA dehydrogenase to recruit damaged mitochondria in PINK1/Parkin-dependent way. On the other hand, OPTN could interact with valosin-containing protein (VCP), an autophagy regulator in autophagosome biogenesis, and promote the formation of VCP-Beclin1 complex to recruit WIPI2 (WD repeat domain, phosphoinositide-interacting protein 2), which could initiate mitophagy.^25,26

Researchers have also explored the regulatory mechanism of mitophagy in different disease models. Severe fever with thrombocytopenia syndrome virus (SFTSV) is an enveloped, single-stranded, negative-sense RNA virus, and its genome consists of three segments including the large, medium, and small RNA segments. Among them, the small RNA segment encodes the nucleoprotein (NP).²⁷ SFTSV NP could interact with Tu translation elongation factor (TUFM), which is located on mitochondria, to translocate into mitochondria. The interaction between SFTSV NP and TUFM could trigger mitophagy to sequester mitochondria into autophagosomes, which induce the degradation of mitochondrial antiviral signaling protein (MAVS) and subsequently inhibit the antiviral innate immunity.²⁸ Cyclic mechanical stretching (CMS) treatment could enhance the survival and the ability of skin repair of adipose-derived stem cells (ADSCs) under oxidative stress. Mechanistically, CMS could upregulate the expression of Piezo1, an evolutionarily conserved cation channel, in ADSCs. The upregulated Piezo1 could promote the mitochondrial respiration, reduce the accumulation of mitochondrial reactive oxygen species (mtROS), and upregulate the expression of PINK1, which enhance the PINK1-dependent mitophagy and thus accelerate tissue regeneration.^29,30 Osteoarthritis could elevate the level of interleukin-1 beta (IL-1β) in chondrocytes, and the elevated IL-1β could reduce the expression of FOXO1, which may suppress PINK1-dependent mitophagy and thus cause the injury of chondrocytes.³¹ Another research has also addressed the role of FOXO1 in regulation of mitophagy in osteoarthritis chondrocytes. It was reported that in osteoarthritis chondrocytes, insulin receptor substrate 2 (IRS2), a key intermediary molecule in the insulin signaling pathway, was downregulated, leading to the suppression of the expression of PI3K/AKT signaling pathway. This suppression of PI3K/AKT signaling pathway could reduce the level of phosphorylated FOXO1, thereby decreasing its interaction with autophagy-related 7 (ATG7) and subsequently inhibiting mitophagy.³² During cancer-cachexia-induced muscle loss, PGAM5 has been demonstrated to exert an important role. Mechanistically, PGAM5 could physically bind to BNIP3 via its NH2-terminal region and then dephosphorylate BNIP3 to inhibit the ubiquitination and proteasomal degradation of BNIP3, which promotes the formation of PGAM5-BNIP3 complex to maintain the mitophagy induced by tumor load.³³

The regulatory mechanism of mitophagy under certain cell status has also been studied. Iron loss could also induce mitophagy.³⁴ Deferiprone, an iron chelator, has been demonstrated to upregulate the expression of hypoxia-inducible factor 1α (HIF-1α) in Huh7 and HepG2 hepatoma cells. The elevated HIF-1α could elevate the level of specific protein 1 and then upregulate the expression of mitochondrial ferritin (FTMT). FTMT precursors are localized in mitochondrial outer membrane, where they interact with NCOA4, a selective cargo receptor for ferritinophagy, which initiates mitophagy to suppress reactive oxygen species (ROS) production and eliminate the damaged mitochondria.³⁵ In the condition of high-fat diet, lipotoxic-damaged hepatocyte could secret small extracellular vesicles (sEVs) enriched with LIMA1 (LIM domain and actin binding 1), an actin-binding cytoskeletal protein containing an LIM structural domain. These LIMA1-enriched sEVs could fuse into hepatic stellate cells, where LIMA1 could subsequently promote the degradation of PINK1, thereby inhibiting the PINK1-dependent mitophagy and thus activating the proliferation of hepatic stellate cells to aggravate the development of liver fibrosis.³⁶ Guo et al. reported that the ataxia-telangiectasia mutated-cell-cycle checkpoint kinase 2 (ATM-CHK2) signaling pathway, a DNA damage response (DDR) pathway, could regulate critical three steps in mitophagy under cellular stress. First, mtROS could phosphorylate ATM at Ser1981, and the phosphorylated ATM could further phosphorylate CHK2 at Thr68. The activated ATM-CHK2 signaling pathway could phosphorylate ATAD3A at Ser371, which may cause the import arrest of PINK1 and stabilize PINK1 located on OMM, thereby promoting mitophagy. Second, the ATM-CHK2 signaling pathway activated by mtROS could phosphorylate OPTN at Ser473, leading to enhancement of targeting of ubiquitinated mitochondria to autophagosomes. Finally, the ATM-CHK2 signaling pathway activated by mtROS could phosphorylate Beclin at Ser90 and Ser93, resulting in promoting the formation of autophagosomal membranes. They demonstrated that ATM-CHK2 signaling pathway plays a critical role in regulating mitophagy.^37,38

NOD-like receptor X1 (NLRX1), a member of the nod-like receptor family, has been found to contain an LIR motif, and NLRX1 could directly bind to LC3 through this LIR motif. NLRX1 and its LIR motif are essential for Listeria monocytogenes-induced mitophagy, which is important for its survival.³⁹ Following mitochondrial protein import stress, NLRX1 is retained in cytosol and recruit RRBP1, a ribosome-binding transmembrane protein of the endoplasmic reticulum. The NLRX1/RRBP1 complex could promote mitophagy by driving LC3 lipidation.⁴⁰ In the pathological condition such as intestinal ischemic reperfusion injury, NLRX1 could elevate the level of Tyr18-phosphorylated FUNDC1 to inhibit the expression of nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 and 2 (NIPSNAP 1 and 2), which upon depolarization of the mitochondrial membrane accumulate on the surface and recruit many autophagy-associated proteins. The decreased level of NIPSNAP 1 and 2 could inhibit mitophagy and thus promote cellular apoptosis.⁴¹

The canonical mitophagy pathways, such as PINK1/Parkin-dependent mitophagy and receptor-dependent mitophagy, target whole mitochondria for lysosomal degradation. Increasing evidence have suggested that selected mitochondrial components could also be targeted for lysosomal degradation via other pathways such as piecemeal mitophagy.⁴² Guerroué et al. reported that LC3C-mediated piecemeal mitophagy is essential for maintenance of the integrity of mitochondrial network at basal growth condition. They also speculated that LC3C-mediated piecemeal mitophagy may contribute to maintenance of mitochondrial homeostasis via specifically removing damaged mitochondrial contact site and cristae organizing system (MICOS) complex component.⁴³ Abudu et al. found that sorting and assembly machinery (SAM) complex protein SAMM50 could act as a receptor for a piecemeal mitophagy of components of the SAM and MICOS complexes. They further demonstrated that SAMM50 could directly interact with Atg8 family protein by canonical LIR motif and with SQSTM1/p62 to mediate basal piecemeal mitophagy, which exerts quality control of MICOS components.^44,45 Researchers identified that the PX-domain-containing protein sorting nexin 10 (SNX10) could act as a negative regulator of piecemeal mitophagy of OXPHOS machinery components.⁴⁶ These results further shed light on the mechanism of mitophagy.

Mitochondrial biogenesis and mitochondrial dynamics influence the regulation of mitophagy

Overview

Mitochondrial fission and fusion are the important part of mitochondrial dynamics.⁴⁷ Mitochondrial fusion is regulated by the activity of three major proteins, including MFN1, MFN2, and optic atrophy 1 (OPA1). MFN1 and MFN2 are located on the OMM, while OPA1 is distributed in the IMM. Mitochondrial fusion begins with MFN1/Mfn2-mediated OMM fusion and ends with OPA1-mediated IMM fusion⁴⁸ (Figure 3A). Dynamin-related protein (DRP1) is the most important pro-fission protein involved in mitochondrial fission, which is localized in the cytosol and exerts pro-fission activity upon binding to receptors on OMM, including mitochondrial fission factor (Mff), fission 1 (fis1), and mitochondrial dynamics proteins 49 and 51 (MiD49 and MiD51). Mitochondrial fission divides the mitochondrion into two daughter mitochondria with unequal membrane potential or different contents⁴⁹ (Figure 3B). Post-translational modifications of DRP1 are crucial for its existence and function.⁵⁰ Kleele et al. identified two distinct types of fission and observed that fission at the periphery region accumulates damaged components within a smaller mitochondrion for mitophagy, whereas fission in the midzone zone is more likely to result in an increase in the mitochondrial population.⁵¹ HSP70 is a protein chaperone that exerts anti-apoptotic function and is associated with tumor development.⁵² It was reported that HSP70 inhibition could decrease the level of phosphorylated DRP1 at Ser616 and concurrently increase the level of phosphorylated DRP1 at Ser637, which impairs mitochondrial dynamics to induce mitochondrial apoptosis.⁵³ The ubiquitin-specific protease 1 (USP1) is a deubiquitinase that could deubiquitinate particular cellular substrate to exert several roles in biological activities. USP1 could deubiquitinate CDK5 to increase the stabilization of CDK5, which could promote the phosphorylation of DRP1 at Ser616 site and subsequently induce mitochondrial fission, thereby resulting in cancer progression.⁵⁴ Recently, an increasing number of studies have shown that mitochondrial dynamics and mitophagy are closely associated with cellular homeostasis.

Figure 3.

Overview of mitochondrial dynamics and mitochondrial biogenesis

(A) Mitochondrial fusion initiates with the approach and subsequent fusion of two individual mitochondria, forming a reversible GTPase-independent molecular tethering, representing MFN homodimeric (MFN1-MFN1) and heterodimeric (MFN1-MFN2) complexes. Then the irreversible GTPase-dependent OMM fusion is initiated, and the mitochondrial fusion process is subsequently completed by the fusion of the IMM facilitated by OPA1. (B) During mitochondrial fission, DRP1 first moves from the cytosol to the OMM, where it forms higher-order complexes with receptors/adaptors, constricting the mitochondrion in a GTPase-dependent manner. Ultimately, the mitochondrion is bisected into two daughter mitochondria with unequal membrane potentials or different content. The mitochondrion with an unstable membrane potential could be the target of mitophagy. (C) During mitochondrial biogenesis, PGC-1α enhances the activity of several transcription factors such as NRF1 to activate mitochondrial transcription factor A (TFAM) and mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M), which regulates the replication and transcription of mtDNA. (D) During mitochondrial trafficking, Miro1 binds to tubulin (kinesin/dynein and TRAK1/2 complexes) via the adaptor protein Milton, and Miro2 binds to actin filaments via myo19. The roles of these two proteins are distinct.

Mitochondrial biogenesis is a complex process that plays a pivotal role in the replication, transcription, and translation of mtDNA. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is the primary regulator of mitochondrial biogenesis, orchestrating the activities of several transcription factors, including nuclear respiratory factors 1 and 2 (NRF1 and NRF2), estrogen-related receptor α (ERRα), cAMP-responsive element-binding protein 1 (CREB1), and FOXO, which could activate mitochondrial transcription factor A (TFAM) and mitochondrial transcription factors B1 (TFB1M) and B2 (TFB2M)^55,56 (Figure 3C). TNF-receptor-associated protein 1 (TRAP1) is a member of the HSP90 chaperone family, which is localized in mitochondria and involved in cancer progression.⁵⁷ TRAP1 silencing could promote the expression of PGC-1α and TFAM, which could promote the mitochondrial biogenesis for the formation of novel functional mitochondria, thereby promoting the metabolic rewiring and cancer progression.⁵⁸

Mitochondrial trafficking, another important aspect of mitochondrial dynamics, allows the targeted relocation of mitochondria in response to fluctuations in energy demand. Mitochondrial Rho guanosine triphosphate hydrolases (GTPases) (Miro proteins), including Miro1 and Miro2, are localized to the OMM and contain two classical EF-hand motifs, which are capable of binding to Ca²⁺. Miro1 plays a specific role in mitochondrial localization and long-distance transport, which utilizes the tubulin cytoskeleton. In contrast, Miro2 plays a more significant role in short-distance transportation, working in conjunction with actin filaments.^48,59,60,61 Miro1 and Miro2 are required for normal mitochondrial cristae architecture and endoplasmic-reticulum-mitochondria contact sites. Miro could also couple MICOS to TRAK protein to ensure the correct distribution of cristae on the mitochondrial membrane.⁶² Armadillo repeat-containing protein 1 (ARMC1), which is dual-localized between the cytosol and the mitochondrial surface, has been found to mediate the assembly of Miro with mitochondrial fission regulator (MTFR). The Miro-MTFR complex could compete with TRAK2 recruitment to mitochondria. When ARMC1 fails to assemble with MIRO and MTFR, an excessive of mitochondrial recruitment of TRAK2 could drive abnormal mitochondrial movement, generating a clustered mitochondrial distribution in the perinuclear region of cells⁶³(Figure 3D).

Mitophagy and mitochondrial fusion

In PINK1/Parkin-dependent mitophagy, Parkin ubiquitinates MFN1 and MFN2 for degradation in a proteasome- and P97-dependent manner. The degradation of MFN1 and MFN2 prevents mitochondrial re-fusion and thus facilitates the progression of mitophagy.⁶⁴ The creation of a MFN2 mutant lacking a PINK1 phosphorylation site (MFN2 AA) revealed that MFN2 AA suppressed the recruitment of Parkin, resulting in the inhibition of mitophagy without impairing mitochondrial fusion.⁶⁵ Phosphorylated caveolin-1 (Cav-1) has been demonstrated to impede the translocation of MFN2 to mitochondria and the recruitment of Parkin by interacting with MFN2.⁶⁶ Pink1/Parkin-mediated phosphorylation and ubiquitination of MFN2 led to its dissociation from the OMM and facilitated mitochondria-ER separation, thereby increasing the availability of other Parkin substrates.⁶⁷ Inhibiting ubiquitin-specific protease 30 (USP30) in cultured neurons led to the ubiquitination of MFN2, segregating damaged mitochondria from the healthy mitochondrial network and enhancing mitophagy.⁶⁸ MORN repeat-containing protein 4 (MORN4) may bind directly to MFN2, facilitating MFN2 S442 phosphorylation via Rho-associated protein kinase 2 (ROCK2), thereby mediating mitophagy.⁶⁹ Yu et al. demonstrated that mitochondrial fusion could promote mitophagy to proportionally reduce mitochondrial mass and ATP production, thereby inhibiting pancreatic tumor cell proliferation in vitro and decreasing tumor volume in vivo.⁷⁰ Lv et al. investigated the mechanism about how high-fat diet (HFD) induces steroidogenic inhibition in TM3 cells, a mouse Leydig cell line, and found that palmitic acid (PA) could induce mitophagy inhibition in TM3 cells. They further demonstrated that promoting mitochondrial fusion could attenuate PA-induced mitophagy inhibition, and MFN2 knockdown could down-regulate the expression of PINK1 and Parkin.⁷¹

OPA1 is also of great importance in the interaction between mitochondrial fusion and mitophagy. In cells with collapsed membrane potential, inactivation of the inner membrane protease OMA1 prevents cleavage of OPA1, delaying mitophagy in the presence of Parkin.⁷² Under hypoxia condition, OMA could regulate the metabolism of colorectal cancer cells. On the one hand, OMA is activated in the hypoxic tumor microenvironment, and the activated OMA promotes the degradation of OPA1, leading to loss of mitochondrial cristae in cancer cells and subsequent downregulation of OXPHOS. On the other hand, the activated OMA could promote the generation of mtROS to stabilize the HIF-1α, thereby promoting the glycolysis of cancer cells.⁷³ OPA1 interacts with FUNDC1 via its Lys70 residues. A mutation of OPA1 at the Lys70 residues disrupts the interplay between OPA1 and FUNDC1, thus promoting mitophagy⁷⁴ (Figure 4A).

Figure 4.

Mitochondrial biogenesis and mitochondrial dynamics influence the regulation of mitophagy

(A) Mitochondrial fusion and mitophagy. (B) Mitochondrial fission and mitophagy. (C) Mitochondrial biogenesis and mitophagy. (D) Mitochondrial trafficking and mitophagy.

Mitophagy and mitochondrial fission

The role of DRP1 in mitophagy remains controversial. Some researches support that DRP1 could promote the mitophagy. Doxorubicin treatment accelerated mitophagy flux, and DRP1 knockdown decreased this mitophagy flux, revealing that mitochondrial fission is required for doxorubicin-induced mitophagy.⁷⁵ In cardiac myocytes, reduced DRP1 inhibited autophagosome formation and autophagic flux at both baseline and in response to glucose deprivation, thereby suppressing mitophagy.⁷⁶ Wang et al. reported that BCL2-like 13 (BCL2L13) phosphorylated DRP1 at the Ser616 site to activate DRP1 and inducing mitophagy in glioblastoma.⁷⁷ Tong et al. demonstrated that in the progression of HFD-induced obesity cardiomyopathy, DRP1 could activate mitophagy in traditional ATG7/LC3-dependent manner in the early phase and in an alternative manner involving Rab9 and Fis1 in the chronic phase, thereby alleviating cardiac dysfunction.⁷⁸ Rahman et al. used C2C12 myoblasts to study the changes of mitochondrial fission and mitophagy during myogenesis. They found that overexpression of DRP1 could accelerate mitophagic flux, and DRP1 knockdown could suppress mitophagy in C2C12 myoblasts.⁷⁹ It has been demonstrated that under hypoxia, DRP1 was overexpressed, and this excessive mitochondrial fission could induce mitophagy in tumor cells, which could attenuate mitochondrial apoptosis in tumor cells and thus promote the survival of tumor cells.⁸⁰ Realgar is a toxic mineral medicine containing arsenic that has potential neurotoxicity. Feng et al. found that arsenic in realgar could promote the DRP1 translocation to mitochondria, where it underwent phosphorylation, which led to the excessive mitochondrial fission in PC12 cells. Moreover, excessive mitochondrial fission could promote mitophagy in PC12 cells, which could exert self-protective role in PC12 cells.⁸¹ DRP1 phosphorylated at serine 616 (p-Drp1Ser616) has been located at mitochondrion and lysosome membrane contact sites by interacting with Rab7, triggering an increase in mitochondria-lysosomal interaction, resulting in PINK1/Parkin-dependent mitophagy and thus exerting anti-apoptosis effect in tumor cells treated with chemotherapy.⁸² Xiong et al. reported that fatty acids uptakes could induce mitochondrial fragmentation by promoting ERK-dependent DRP1 phosphorylation at S616, which could contribute DRP1-dependent mitophagy to protect mitochondrial integrity, consequently promoting the progression of cancer and remodeling the cancer metabolism.⁸³ Citrullination is one of the post-translational modifications of DRP1. Zhu et al. reported that during metabolic-dysfunction-associated steatohepatitis (MASH) development, the citrullination of DRP1 at arginine-114 (R114) site is significantly decreased, which decreases the stability of DRP1 and thus impairs its ability of regulating mitophagy.⁸⁴ PPA2, the inorganic pyrophosphatase, is a matrix-localized protein that is involved in mitochondrial function. It was demonstrated that under stress conditions, PPA2 could promote the recruitment of DRP1 to the fission site of mitochondria, which could facilitate peripheral mitochondrial fission and then segregate dysfunctional daughter mitochondria, ultimately activating mitophagy to degrade the dysfunctional daughter mitochondria.⁸⁵ Oleinik et al. proposed that ceramide analog D-erythro-14-(1-pyridinium)-N-octadecanoyl-sphingosine selenite (LCL768) could induce ceramide synthase 1 (CerS1)-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which was dependent on DRP1 activation via nitrosylation.⁸⁶

Nevertheless, some studies have proposed an alternative viewpoint, suggesting that DRP1 is not essential for mitophagy and may even impede it. By conducting in vitro and in vivo experiments, it was found that ablation of DRP1, which impairs mitochondrial fission could increase mitophagy and cause the complete loss of mitochondria.⁸⁷ Yamashita et al. reported that DRP1 is dispensable for mitophagy,⁸⁸ and a recent study showed that the loss of DRP1 even increased the recruitment of Parkin and the rate of mitophagy.⁸⁹ Li et al. reported that knockdown of DRP1 improved mitophagy in post-operative aged rats, while promoting mitophagy in turn effectively reduced the expression and phosphorylation of DRP1, suggesting a reciprocal regulation between mitochondrial fission and mitophagy.⁹⁰ It was demonstrated that during the mitotic arrest, a clear induction of mitophagy was observed and higher rates of mitophagy were detected in siDRP1-treated HeLa cells.⁹¹ Yoo et al. demonstrated that under stress condition, such as hypoxia, FKBP8-mediated mitochondrial fragmentation is independent of DRP1, and this kind of mitochondrial fragmentation is required for mitophagy.⁹² The specific underlined mechanism of this phenomenon needs further investigation (Figure 4B).

Mitophagy and mitochondrial biogenesis

Parkin plays a role in mitochondrial biogenesis by interacting with parkin-interacting substrate (PARIS), an inhibitor of TFAM, mtDNA, and PGC-1α.⁹³ Knockdown of general control of amino acid synthesis 5-like 1 (GCN5L1) enhanced mitophagy in mouse embryonic fibroblasts (MEFs). However, the augmented mitophagy flux does not result in a reduction of mitochondrial content, as PGC-1α is also activated to promote mitochondrial biogenesis, suggesting the acceleration of mitochondrial turnover in GCN5L1-deficient MEFs.⁹⁴ Similarly, during myogenic differentiation, mitophagy was markedly elevated to facilitate the clearance of obsolete mitochondria, while mitochondrial biogenesis, driven by PGC-1α, was initiated to produce new mitochondria, thereby updating the mitochondrial content.⁹⁵ In human neuroblastoma SH-SY5Y cells, following mitophagy, transcriptional factor EB (TFEB) was activated and upregulated, resulting in an increase in the expression of PGC-1α.⁹⁶ Lynch et al. demonstrated that cisplatin impairs mitophagy but PGC-1α can counteract this impact and even enhance the intrinsic mitophagy process, which is beneficial for kidney protection.⁹⁷ Researchers discovered that, in response to oxidative stress, the sirtuin 1 (SIRT1) activator, SRT-1720, upregulated the expression of PINK1/Parkin in intestinal epithelial cells by activating the SIRT1/PGC-1α pathway, thereby initiating mitophagy.⁹⁸ Protein phosphatase 2A (PP2A) regulatory subunit B55α (PP2A-B55α) is an identified serine and threonine phosphatase in eukaryotic cells.⁹⁹ Cianfanelli et al. found that upon mitochondrial damage, PP2A-B55α could restrict mitochondria priming for recognition by the autophagy machinery by affecting phosphorylated ubiquitin chains and mitophagy receptors, while promoting TFEB activation and nuclear translocation to sustain the execution of Parkin-dependent mitophagy. Furthermore, PP2A-B55α could promote the expression of PARIS to inhibit the mitochondrial biogenesis.¹⁰⁰ Ai et al. presented a small molecule, PR-364, developed to selectively activate Parkin. Parkin activated by PR-364 could promote mitophagy and mitochondrial biogenesis and improve mitochondrial function, resulting in an improvement of cardiac function and survival of myocardial infarction patients.¹⁰¹ Another research also emphasized the role of balance between mitophagy and mitochondrial biogenesis in myocardial ischemia. Yang et al. found that checkpoint kinase 1 (CHK1) could interact with SIRT1 and phosphorylate SIRT1 at Thr530 site to inhibit the degradation of SIRT1, leading to facilitation of mitochondrial renewal by promoting mitochondrial biogenesis and mitophagy.¹⁰²

The balance also exists between mitochondrial biogenesis and receptor-dependent mitophagy. In acute cardiac ischemia-reperfusion injury, FUNDC1 deficiency reduced transcription of PGC1α, NRF1, and TFAM, showing FUNDC1-dependent mitophagy plays a key role in mitochondrial turnover through mitochondrial biogenesis.¹⁰³ It has been reported that insulin-like growth factor 1 (IGF-1) may couple mitochondrial biogenesis with the induction of BNIP3, thereby improving cellular survival under metabolic stress.¹⁰⁴ In brown adipose tissue (BAT), FUNDC1-dependent mitophagy is coupled with the PGC-1α/NRF1 pathway, as evidenced by the specific reduction of FUNDC1 mRNA and protein levels caused by PGC-1α knockdown in adipocytes.¹⁰⁵

However, the balance can be disturbed under certain pathological conditions. Yu et al. observed that PGC-1α knockdown activates mitophagy, potentially contributing to the development of pre-eclamptic placentas.¹⁰⁶ Similarly, researchers have discovered that the combination of a PGC-1α inhibitor and cisplatin could result in excessive mitophagy and subsequent cell death in oral cancer cells in vitro.¹⁰⁷ However, Hsu reported that mitochondrial biogenesis could coordinate with mitophagy to promote breast cancer metastasis. They demonstrated that DEAD-box polypeptide 3, X-linked (DDX3) is stabilized by type 1 arginine methyltransferase (PRMT1), and DDX3 could facilitate the expression of PINK1 and PGC1α, which could coordinate mitochondrial biogenesis and mitophagy to promote breast cancer progression.¹⁰⁸ These results revealed that in cancer cells, the balance between mitochondrial biogenesis and mitophagy remains unclear and warrant further investigations. Palioura et al. reported that peroxisome proliferator-activated receptor δ (PPARδ) activation could stimulate mitochondrial biogenesis, resulting in the alleviation of excessive mitophagy in desmin-deficient mice¹⁰⁹ (Figure 4C).

Mitophagy and mitochondrial trafficking

During PINK1/Parkin-dependent mitophagy, phosphorylation of Miro by PINK1 facilitates its degradation by the proteasome, which contributes to the sequestration of damaged mitochondria prior to mitophagy.¹¹⁰ Furthermore, in human dopaminergic neuroblastoma cells, mitochondrial damage results in the rapid and consistent PINK1/Parkin-dependent ubiquitination of Miro, leading to its degradation by the proteasome.¹¹¹ Post-translational modification of Miro is important for its stabilization and degradation. Phosphorylation of Miro at Ser156 enhances Parkin-Miro interaction, ubiquitination and degradation of Miro, recruitment of Parkin to the OMM, and arrest of mitochondrial motility. In contrast, phosphorylation of Miro at the Thr298 and Thr299 sites suppresses Parkin-induced Miro ubiquitination, Parkin recruitment, and Parkin-dependent arrest of mitochondrial motility¹¹² (Figure 4D).

Recently, several studies have provided further insights into the biological functions of Miro. Safiulina et al. found that when mitochondrial damage occurs, Parkin translocation requires the intact Ca²⁺-sensing EF-hand motif of Miro1.¹¹³ López-Doménech et al. also demonstrated that the ubiquitination and degradation of Miro1 are crucial for the stabilization of Parkin on the OMM and the subsequent clearance of damaged mitochondria.¹¹⁴ Kam et al. found that in Alzheimer disease, AβO could upregulate the level of ROS to promote Parkin-dependent mitophagy and decrease the level of the expression of Miro1. They further demonstrated that overexpression of Miro1 could ameliorated AβO-induced mitophagy.¹¹⁵ Li et al. found that miR-27-3p was highly expressed in M1-macrophage-derived exosomes. miR-27-3p could suppress the expression of Miro1, which impairs mitophagy, resulting in the development of insulin resistance.¹¹⁶ Miro2 has also been found to be involved in the regulation of mitophagy. It was demonstrated that miR-351-5p could suppress the expression of Miro2 in adult hippocampal neural progenitor, and the downregulated Miro2 could induce excessive mitophagy by increasing the level of PINK1 and Parkin, which induce the cell death of hippocampal neural progenitor and thus contribute to the pathological condition in Alzheimer disease.¹¹⁷

In a summary, mitochondrial fusion has been found to hinder mitophagy, whereas mitochondrial fission creates favorable conditions for the initiation of mitophagy. Mitochondrial biogenesis and mitophagy represent two opposing processes that work in concert to facilitate mitochondrial turnover. Miro proteins are significantly associated with mitochondrial trafficking, and suppression of mitochondrial trafficking could spatially confine damaged mitochondria, thereby facilitating the execution of mitophagy.

Mitophagy acts as a double-edged sword for digestive system cancer

As the hub of cellular energy, mitochondria play a critical role in tumorigenesis and cancer progression. Mitophagy is essential for mitochondrial homeostasis. Digestive system cancer includes colorectal cancer (CRC), gastric cancer (GC), esophageal cancer (EC), liver cancer, and pancreatic cancer. Digestive system cancer brings the heavy burden for human beings. Understanding the mechanisms of carcinogenesis and progression of digestive system cancer is essential for the prevention and treatment. The following article will review the research progress of mitophagy in different types of cancers.

Gastric cancer

In terms of gastric cancer, there were over 968,000 new cases of stomach cancer in 2022 and close to 660,000 deaths. Gastric cancer ranks fifth in terms of both incidence and mortality worldwide.^118,119 Gastric cancer progresses rapidly, and many patients have lymph node metastasis or even distant metastasis at the time of diagnosis. In addition, patients with gastric cancer often develop treatment resistance. Therefore, it is important to further study the mechanism of gastric cancer progression and treatment resistance. To date, several studies have reported that mitophagy plays an important role in gastric cancer development, progression, and drug resistance.

Mitophagy could regulate the occurrence and progression of gastric cancer

Some studies have reported that mitophagy can inhibit the proliferation and invasiveness of gastric cancer. Marzetti et al. recruited 18 gastric adenocarcinoma patients (including nine GC patients with cachexia and nine GC patients without cachexia) and 9 controls. Compared to the control group, the expression of PINK1 and Parkin were found to be lower in cancer patients.¹²⁰ In MKN-45 and SGC-790 cell lines, methionine deficiency could inhibit the expression of lncRNA PVT1 and the interaction between lncRNA PVT1 and DNMT1 to demethylate the promoter region of BNIP3, which activates mitophagy to exert anti-tumor effects.¹²¹ Overexpression of gamma-glutamyltransferase 7 (GGT7), a protein involved in carcinogenesis, significantly suppresses GC cell proliferation, migration, and invasiveness in vitro and suppresses xenograft growth and lung metastasis in vivo. This is because GGT7 directly binds to RAB7 to induce mitophagy, thereby inhibiting ROS production and MAPK signaling.¹²² Shida et al. reported that under hypoxia, cell survival and invasion ability of MKN45 cells were significantly weaker than that of 44As3 and 58As9 cells, and hypoxia-induced mitophagy was only observed in MKN45 cells, suggesting that mitophagy may inhibit the aggressiveness of GC cells under hypoxia.¹²³ β-lactamase-like protein (lactamase-β/LACTB), a mammalian mitochondrial-membrane-associated protein derived from bacterial penicillin-binding protein and β-lactamases, has been found to involve in regulating the apoptosis of GC cells. Mechanistically, knockdown of LACTB could activate PINK1/Parkin-mediated mitophagy and subsequently induce apoptosis of GC cells.¹²⁴ Ma et al. reported that succinate, a tricarboxylic acid cycle intermediate, could regulate the anti-tumor immune response. They demonstrated that succinate could enhance the mitochondrial fitness by promoting BNIP3-mediated mitophagy, resulting in boosting CD8⁺ T cell antitumor activity.¹²⁵

On the other hand, some studies suggest that mitophagy promotes the progression of gastric cancer. The researchers found that Helicobacter pylori, the independent risk factor for gastric cancer, could initiate mitophagy primarily through CagA, to reduce NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome activation, leading to immune surveillance evasion of infected cells, thereby contributing to the development of gastric cancer.¹²⁶ However, these results are contradictory with the results showed by another research. Zhang et al. found that Helicobacter pylori could inhibit mitophagy to maintain mitochondrial homeostasis, which may promote the pro-tumor effect of H. pylori, suggesting the dual role of mitophagy in H. pylori-induced GC occurrence.¹²⁷ DAZ-associated protein 1 (DAZAP1), a splicing regulator linked to various malignancies, has been found that could promote the progression of gastric cancer stem cells (GCSCs). Mechanistically, DAZAP1 could upregulate the expression of ULK1 through regulating nonsense-mediated mRNA decay, thus activating mitophagy and enhancing OXPHOS to maintain the stemness of GC cells.¹²⁸ Ras homolog family member T1 (RHOT1), a mitochondria-associated protein, has been reported to be involved in the progression of GC. Researchers found that silencing RHOT1 could suppress the expression of PINK1 and Parkin, which could inhibit mitophagy to suppress the proliferation and aggressiveness of GC cells.¹²⁹ Sung et al. showed that TNF could boost the activity of Jun N-terminal kinase (JNK) to raise the expression of Parkin, subsequently triggering mitophagy to eliminate the damaged mitochondria, thereby preventing cell death.¹³⁰ Tanaka et al. showed that under hypoxia, knockdown of HIF-1α in GC cells could decrease the expression of BNIP3 and BNIP3L and induce the excessive ROS production, thereby inducing the apoptosis of GC cells.¹³¹

Taken together, these results suggest that mitophagy exerts a dual role in regulating the occurrence and progression of gastric cancer.

Mitophagy is involved in drug resistance of gastric cancer

Drug resistance is one of the most difficult problems for clinicians to overcome. Some studies have suggested that mitophagy is involved in drug resistance in gastric cancer. In AGS and MKN-45 cells, knockdown of TRPM2, a member of the transient receptor potential family, could impair mitochondrial metabolism and mitophagy and sensitize GC to paclitaxel and doxorubicin, suggesting that mitophagy may contribute to GC progression and drug resistance.¹³² The researchers found that metformin could significantly promote cell proliferation of AGS cells and SGC-7901 cells, thereby protecting GC cells from cisplatin cytotoxicity, by activating PINK1/Parkin-dependent mitophagy in an AMPK-signaling-dependent manner.¹³³ Natriuretic peptide receptor A (NPR1), a major receptor for atrial natriuretic peptide, has been shown to be closely associated with cisplatin resistance in gastric cancer by reducing ubiquitination-mediated PARL degradation to inhibit mitophagy-dependent ferroptosis.¹³⁴ He et al. selected oxaliplatin-resistance GC cells and analyzed the tumor tissue from these GC patients by utilizing single-cell sequencing. They found that oxaliplatin-resistance GC cells actively remodel the tumor microenvironment by increasing extracellular matrix stiffness. The high matrix stiffness could activate the Ras homolog family member A (RhoA)/ROCK signaling pathways of mesenchymal stromal cells to restore the mitochondrial function of GC cells, thereby suppressing mitophagy in GC cells and improving GC cells survival.¹³⁵

Altogether, these results revealed that mitophagy plays an important role in development of drug resistance in gastric cancer.

Treatment for gastric cancer involving mitophagy

Some compounds derived from natural plants and traditional Chinese medicine as well as several existing drugs have been found to exert anti-tumor effects in gastric cancer by regulating mitophagy. A bioactive compound derived from ginger, 8-paradol, may also exert anti-tumor effects by activating PINK1/Parkin-dependent mitophagy.¹³⁶ Chen et al. found that dehydrocostus lactone (Dehy), a sesquiterpenoid compound extracted from the dried roots of Aucklandia lappa Decne, could significantly inhibit the proliferation of GC cells. Mechanistically, Dehy could promote ROS production and mitochondrial depolarization, which may activate mitophagy via the PINK1-Parkin signaling axis and thus promote the elimination of damaged mitochondria, resulting in apoptosis of GC cells.¹³⁷ Ailanthone, the main bioactive component of the extract obtained from the desiccated bark of Ailanthus altissima (Mill.) Swingle, has been found that could significantly inhibit the progression of GC in vitro and in vivo. It was further demonstrated that Ailanthone could inhibit mitophagy by suppressing the expression of NIX and Parkin and reduce the stability of HIF1α by promoting its deacetylation, resulting the ROS accumulation and mitochondrial-dysfunctional-mediated apoptosis.¹³⁸ Ghosh et al. reported that in low PINK1-expressing gastric cancer cells, disruption of mitochondrial electron transport chain (ETC) by Indomethacin treatment combined with mitochondrial fission inhibition could significantly reduce the viability of GC cells compared with that of normal gastric epithelial cells, suggesting PINK1 could be involved in mechanism of anti-GC drugs.¹³⁹

In recent years, researchers have proposed several treatment strategies, using methods such as advanced materials to enhance the therapeutic effect of gastric cancer. ZIF-90 was a kind of zeolite imidazole framework that exhibits mitochondrial targeting and tumor response ability.¹⁴⁰ Qiu et al. loaded ZIF-90 with resveratrol to synthesize a drug-delivery system named Res@ZIF-90. They found that Res@ZIF-90 could significantly reduce the expression of PINK1, which inhibits mitophagy to disrupt the mitochondrial homeostasis in GC cells, thus suppressing the progression of GC.¹⁴¹ Lo et al. presented a one-shot formulation of Afatinib, a broad-spectrum tyrosine kinase inhibitor, and miR-125. This formulation comprised solid lipid nanoparticles modified with mitochondrial targeting peptide and estimated glomerular filtration rate (EGFR)-directed ligand. They further demonstrated that this formulation could regulate several pathways in AGS cells such as mTOR/HIF1-α/HK2/LDHA pathways and inhibit glycolysis and mitochondrial OXPHOS. It could also activate PINK1/Parkin-mediated mitophagy to promote the apoptosis of AGS cells.¹⁴² Superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as promising tools for integrated cancer diagnosis and therapy,¹⁴³ and WSGC peptide, a 40-amino acid polypeptide derived from apoC-III, has been demonstrated to have the capability of targeting tumor cells.¹⁴⁴ Song et al. investigated the molecular mechanism by which SPIONs loaded with the WSGC peptide (WSGC@FA@PEG/PEI-SPIONs) modulate chemotherapy resistance in GC. They demonstrated that WSGC peptide could inhibit the Notch signaling pathway to inhibit PINK1/Parkin-dependent mitophagy, thereby suppressing the proliferation and invasiveness of GC cells. These findings provide more insights for development of polypeptide-based anticancer therapies.¹⁴⁵

In conclusion, these results demonstrated that therapeutic approaches involving mitophagy could be promising treatment options, and it is worthy of further investigations (Figure 5).

Figure 5.

Mitophagy and gastric cancer

Mitophagy exerts a dual role in regulating the occurrence and progression of gastric cancer and is significantly associated with development of drug resistance in gastric cancer. Mitophagy-targeted therapeutic approaches could be promising options for gastric cancer patients.

Colorectal cancer

According to the statistics reported in 2024, more than 1.9 million new cases of colorectal cancer (including anal cancers) and 904,000 deaths were estimated to occur in 2022. Colorectal cancer ranks in third place in terms of incidence but second in terms of mortality. Furthermore, early-onset colorectal cancer (<50 years) is of increasing interest globally.^118,146

The role of mitophagy in CRC has garnered significant attention from researchers. For example, Zhang et al. established a prognosis prediction signature based on 10 mitophagy-related genes, and they classified CRC patients into high-risk and low-risk groups based on this signature, suggesting a poorer prognosis in the high-risk group.¹⁴⁷ Weng et al. also performed their mitophagy-associated signature and divided CRC patients into high-risk and low-risk groups. They found that compared to patients in the high-risk group, patients in the low-risk group had a higher enrichment of active immune cells.¹⁴⁸ Gao et al. retrieved and annotated a total of 14,719 cells from eight samples in the single-cell RNA sequencing (scRNA-seq) GSE132465 dataset and they found that mitophagy-related pathways were uniformly activated in cancer cells, suggesting that mitophagy is significantly associated with CRC.¹⁴⁹ Since the high incidence of CRC and the close relationship between CRC and mitophagy, investigating the mechanism of how mitophagy is involved in the development, progression, and drug resistance of CRC may provide more useful information for clinical practice.

Mitophagy could affect the occurrence and development of colorectal caner

Some studies supported that mitophagy could inhibit the progression of colorectal cancer. D'Onofrio reported that the dietary metabolite δ-valerobetaine could cause decreased mitochondrial membrane potential and lower expression of SIRT3 to induce mitochondrial dysfunction and cellular apoptosis in SW480 and SW620 cells through activation of PINK1/Parkin-dependent mitophagy.¹⁵⁰ During tumorigenesis, enhanced mitophagy in intestinal epithelial cells could increase lysosome membrane permeabilization, which enhances major histocompatibility complex (MHC) class I presentation and activation of CD8⁺ T cells, thereby promoting anti-tumor immunity.¹⁵¹ CRC patients with KRAS mutation usually have a poor prognosis. However, Iskandar reported that hyperactivated mutant KRAS in CRC cells could drive mechanistic target of rapamycin kinase complex 2 (MTORC2)-mediated phosphorylation of AKT serine/threonine kinase (AKT) at Ser473. Phosphorylated AKT-Ser473 increases ROS production, activates DRP1-mediated mitochondrial fission, and stabilizes VDAC, leading to mitophagy and cell death.¹⁵² Yang et al. investigated the interaction between Spalt-like transcription factor 4 (SALL4), a critical factor for self-renewal ability and pluripotency of stem cells,¹⁵³ and the ABCB6 gene, which is a member of the B subfamily of ATP-binding cassette (ABC) transporters.¹⁵⁴ They found that SALL4 could activate ABCB6 transcription to inhibit ferroptosis in colon cancer by preventing mitophagy, leading to cancer progression.¹⁵⁵ Cellular retinoic acid binding protein 2 (CRABP2) has been found to be involved in chemotherapy resistance in cancer,¹⁵⁶ while its role in CRC progression remains unclear. Tian et al. investigated that CRABP2 could downregulate the expression of AFG3L2, a mitochondrial m-AAA protease,¹⁵⁷ which could block the AFG3L2-mediated induction of PINK1 degradation and subsequently enhance PINK1-dependent mitophagy, leading to suppression of CRC metastasis.¹⁵⁸ USP14, a member of the deubiquitinating enzymes, has been demonstrated to promote CRC progression and oxaliplatin resistance. Researchers found that USP14 could directly deubiquitinate BAG4 at Lys403 site to protect BAG4 from proteasomal degradation. Stabilized BAG4 could hinder the recruitment of Parkin, thereby inhibiting Parkin-dependent mitophagy and promoting CRC progression and oxaliplatin resistance.¹⁵⁹

Post-transcriptional and post-translational modifications of mitophagy-related genes could influence mitophagy activity and subsequently affect the development and progression of CRC. Wang et al. reported that piwi-interacting RNAs 823 (piR-823) bound directly to PINK1 and promoted the ubiquitination and degradation of PINK1, thereby inhibiting apoptosis and maintaining mitochondrial function and quantity in HCT116 and DLD-1 cells.¹⁶⁰ USP26, a member of the deubiquitinase family of ubiquitin-specific proteases, has been shown to promote deubiquitylation of Parkin at lysine 129 (K129) residue, leading to reduced activity of Parkin-dependent mitophagy and ultimately promoting CRC development and progression.¹⁶¹

As the primary site of energy production, mitochondria obviously affect the cellular metabolism of cancer cells. Yin et al. reported that PINK1 overexpression could promote mitophagy, decrease glycolysis, and increase mitochondrial respiration through activation of the p53 signaling pathway, resulting in inhibition of colon tumor growth.¹⁶² Tang et al. reported that upregulated GPR176, a member of G-protein-coupled receptors, was positively associated with CRC proliferation and poor survival. Mechanistically, the GPR176/GNAS complex activates the cAMP/PKA signaling pathway and phosphorylates BNIP3L to inhibit mitophagy, leading to CRC development and progression.¹⁶³

However, other researches have shown that mitophagy may contribute to the development and progression of colorectal cancer. Several mitophagy-related targets that are responsible for the development and progression of CRC have been identified. Overexpression of mammalian STE20-like kinase 1 (Mst1), one of the components of the Hippo signaling pathway, could inhibit CRC cell growth and migration and promote cellular apoptosis by activating JNK/p53 signaling pathway to suppress BNIP3-dependent mitophagy.¹⁶⁴ Recent research has shown that mefloquine, which targets RAB5/7 involved in early and late lysosome formation, disrupts mitochondrial function and inhibits mitophagy, which effectively eliminates cancer stem cells (CSCs), suggesting that mitophagy may be important for CSC survival.¹⁶⁵ The researchers found that knockdown of DJ-1, a neuroprotective protein, could suppress CRC survival, migration, and colony formation. Mechanistically, DJ-1 knockdown could inhibit mitophagy, leading to a failure to remove damaged mitochondria in metastatic CRC cells.¹⁶⁶ As described above, mitochondria play a critical role in cancer cell metabolism and the regulation of cellular trace elements. Devenport et al. found that under nutrient-rich conditions, inhibiting mitophagy could suppress CRC cell proliferation, suggesting that mitophagy may be necessary for CRC proliferation.¹⁶⁷ Under hypoxia, mitochondrial Lon, a multi-function and stress-induced protein involved in protein quality control and stress response pathways in mitochondria, has been demonstrated to be upregulated and regulate the FUNDC1-dependent mitophagy. Mechanistically, overexpressed Lon could induce the increase in phosphorylation level of ULK1, which promotes the phosphorylation of FUNDC1 at site Ser17 and subsequent formation of ULK1-FUNDC1 complex. Elevated level of p-FUNDC1-Ser17 could promote the mitophagy to benefit cancer cell survival.¹⁶⁸ Another research also reported the role of ULK1-FUNDC1-dependent mitophagy in CRC. Chen et al. found that knockdown PPA1, an essential metabolic enzyme overexpressed in CRC,¹⁶⁹ could attenuate proliferation, suppress metastatic behaviors, and reverse EMT progression of CRC cell. Mechanistically, knockdown PPA1 could reduce the phosphorylation of AMPK at Thr172 site, which decreases the phosphorylation of ULK1 at Ser467 and Ser555 sites and the phosphorylation of FUNDC1 at Ser17, leading to suppression of mitophagy and ultimately inducing the apoptosis of CRC cells.¹⁷⁰ Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8), a ubiquitin-like protein that could conjugate and activate the E3 ligase, has been reported to be associated with CRC distant metastasis. It was further demonstrated that NEDD8 depletion could attenuate the exacerbated mitophagy in Tregs in surgically stressed mice, thereby inhibiting the CRC lung metastasis in mice.¹⁷¹

Altogether, these results suggest mitophagy affects the occurrence and progression of colorectal cancer through dual effect.

Mitophagy is associated with the efficacy of colorectal cancer treatment

Chemotherapy and radiotherapy are the basis of colorectal cancer treatment. In recent years, targeted therapy and immunotherapy have attracted extensive attention. However, these treatments are confronted with several problems such as drug resistance and poor response of some patients. To improve the effectiveness of CRC treatment, researchers have investigated whether mitophagy could be associated with the efficacy of colorectal cancer treatment.

Doxorubicin, a DNA-damaging agent, is widely used in cancer therapy. The researchers found that the level of mitophagy and the expression of BNIP3L in CSCs were significantly increased after doxorubicin treatment. Furthermore, silencing BNIP3L could significantly suppress mitophagy in CSCs and sensitize CSCs to doxorubicin, suggesting that mitophagy may contribute to the development of doxorubicin resistance.¹⁷² The microbial metabolite sodium butyrate (NaB), a derivative of short-chain fatty acids (SCFAs), has been found to inhibit CRC cell proliferation and promote CRC cell apoptosis by enhancing the activity of mitophagy. Combination treatment of NaB with 5-fluorouracil (5-FU) has greater efficacy than 5-FU alone.¹⁷³

Radiotherapy is another important method of tumor treatment, but radiotoxicity is becoming a serious problem for all clinicians. Some researchers reported that metformin could alleviate radiotherapy-induced acute and chronic gastrointestinal toxicity by activating AMPK-dependent mitophagy through promoting degradation of Kelch-like ECH-associated protein 1 (Keap1) to stabilize and activate nuclear factor, erythroid 2-like 2 (Nrf2).¹⁷⁴ The ability to repair DNA damage is important for the development of radioresistance. Wei et al. found that in CRC cells with mitochondrial dysfunction, SIRT3 is overexpressed, leading to excessive activation of PINK1/Parkin-dependent mitophagy, which enhances radiation-induced DNA damage repair to promote tumor cell resistance to radiation.¹⁷⁵

Microsatellite stable (MSS) CRC exhibit poor responsiveness to immunotherapy. Wang et al. found that Shen Qi Yi Chang, a traditional Chinese prescription, could promote mitophagy in dendritic cells via the PINK1/Parkin-dependent pathway to enhance the efficacy of PD-1 inhibitors against MSS CRC, suggesting that mitophagy may also influence the efficacy of immunotherapy.¹⁷⁶

In summary, mitophagy is closely associated with drug resistance and poor responsiveness to treatment in CRC patients.

Mitophagy is a potential therapeutic target for colorectal cancer

Several therapeutic strategies have been shown to exert anti-tumor effects in CRC by targeting mitophagy. In CRC, overexpression of protein disulfide isomerase (PDI) increased the risk of metastasis and poor prognosis in CRC patients and inhibited radiotherapy-/chemotherapy-induced cell death. Mechanistically, PDI could directly interact with the mitophagy receptor PHB2 and competitively block the binding between PHB2 and LC3II, leading to inhibition of mitophagy. PDI is a promising target for sensitizing radiotherapy/chemotherapy.¹⁷⁷ Aloe gel polysaccharide (AGP) is a type of glucomannan and is the main chemical constituent in Aloe. Researchers found that AGP could induce the excessive production of ROS to upregulate the expression of PINK1 and Parkin, thereby activating mitophagy and subsequently inhibiting proliferation of CRC cells.¹⁷⁸ In vitro transcribed (IVT) mRNA has been a rapid method for nucleic acid drug production. Feng et al. constructed an oncolytic IVT mRNA that could trigger mitophagy and utilized the permuted intron-exon (PIE) splicing circularization strategy and lipid nanoparticle (LNP) encapsulation to reduce the immunogenicity of the mRNA and enable the delivery to eukaryotic cells in vivo. This engineered RNA-LNPs could prevent the tumorigenesis of colon adenocarcinoma and improve the survival of patients.¹⁷⁹ Wang et al. reported that they developed an azocalix[4]arene-modified supramolecular albumin nanoparticle that could co-deliver hydroxychloroquine and a mitochondria-targeting photosensitizer. They further demonstrated that the combination of chloroquine and photosensitizers could coordinately regulate mitophagy in CRC cells, thereby driving tumor cell death.¹⁸⁰ Bacterial extracellular vesicles (BEVs) are membrane vesicles released from both gram-positive and gram-negative bacteria, with sizes ranging from 20 to 400 nm.¹⁸¹ It was reported that BEVs, derived from Escherichia coli, strain-A5922, were utilized as therapeutic tools for the treatment of HT-29 colon cancer cells. Researchers further demonstrated that BEVs could induce mitophagy in HT-29 to produce adenocarcinomic cytotoxicity and inhibit cell growth.¹⁸²

Several compounds, such as that extracted from traditional Chinese medicine and plants, have been identified as anti-cancer drugs via targeting mitophagy. Oxymatrine, extracted from the Chinese herb Radix sophorae tonkinensis, promoted the translocation of Parkin to the mitochondria and activated mitophagy to suppress inflammasome activation, thus exerting an anti-cancer effect.¹⁸³ Thymoquinone, another natural compound, has also been shown to suppress migration of HT-29 cells by inducing expression of mitophagy-related genes and reducing angiogenesis.¹⁸⁴ Tong-Xie-Yao-Fang, another traditional Chinese prescription, has also been reported to activate PINK1/Parkin-dependent mitophagy, resulting in suppression of colitis-associated colorectal cancer (CAC) progression.¹⁸⁵ Yang et al. designed and synthesized the enantiopure analogue 6, a kind of plant hormone, which could act as a mitophagy inhibitor and has potent and selective cytotoxicity against CRC cells but not normal colon epithelial cells.¹⁸⁶ Jiang et al. reported that cirsiliol, a type of flavonoid found in many plants, could inhibit cell viability and the ability of colony formation and wound healing. To exert these effects, cirsiliol decreased mitochondrial membrane potential, increased ROS production, and disrupted mitochondrial morphology by suppressing the expression of mitophagy-related proteins such as PINK1 and Parkin via STAT3 signaling.¹⁸⁷ Zhang et al. designed and synthesized a panel of ferrocenyl-substituted curcumin derivatives. They found that compound 3F could inhibit proliferation of CRC cells CT26 and SW480 by regulating the expression of PINK1 and Parkin.¹⁸⁸ Polyphyllin V, a steroidal saponin extracted from Paris polyphylla, has been demonstrated to induce mitophagy to enhance ROS production to suppress CRC cell growth.¹⁸⁹ Radiation-induced intestinal injury is a major problem in CRC patients receiving radiotherapy. It was reported that licochalcone D (LCD), a bioactive compound derived from licorice, could stabilize SIRT3 to induce mitophagy, which could eliminate the radiation-produced ROS and thus ameliorate DNA damage and prevent cellular apoptosis.¹⁹⁰ Su et al. reported that compounds isolated from Taxodium ascendens exert inhibitory effect on CRC cells. They further demonstrated that the compound 12, one of the compounds isolated from T. ascendens, could downregulate mitophagy to suppress RC cell proliferation.¹⁹¹ Ginsenosides, active components of traditional Chinese herbal medicine Panax ginseng, have been reported to exert antitumor effects on various cancers.¹⁹² Sun et al. have studied the antitumor effect of representative ginsenoside Rg3 on colon tumor, and they found that Rg3 could exert an inhibitory effect on colon cancer cell via activating Parkin-dependent mitophagy.¹⁹³ Carnitines are amino acid derivatives abundant in food of animal origin, and Donisi et al. found that treatment of l-carnitine and acetyl-l-carnitine could facilitate the PINK1/Parkin-dependent mitophagy, which could promote CRC cells apoptosis.¹⁹⁴

In conclusion, these results demonstrated that mitophagy is a potential therapeutic target for colorectal cancer, and further investigations are warrant (Figure 6).

Figure 6.

Mitophagy and colorectal cancer

Mitophagy affects the occurrence and development of colorectal cancer through dual effect and is closely associated with drug resistance and poor responsiveness to treatment in colorectal cancer patients. Further investigations about mitophagy-targeted therapy are still warranted.

Esophageal cancer

Esophageal cancer is the eleventh most common cancer and the seventh leading cause of cancer-related deaths worldwide, with an estimated 511,000 new cases and 445,000 deaths in 2022. In the highest region for esophageal cancer, approximately 90% of patients with esophageal cancer have esophageal squamous cell carcinomas.^118,195 The two main histological subtypes are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), with ESCC making 90% of all cases. The overall prognosis of EC patients remains poor.^196,197 Persistent effort on understanding the mechanism of EC initiation and progression and investigating the reasons for drug resistance are crucial for developing efficient and precise therapeutic strategies. As a vital process for maintaining cellular homeostasis, mitophagy has also been found to involve in EC initiation and progression.

Mo et al. investigated the relationship between mitophagy-related genes (MRGs) and ESCC. Using single-cell RNA-sequence analysis and machine learning algorithm, 13 key MRGs were selected, and prognostic model was constructed based on these 13 MRGs. The prognostic model exhibits high accuracy and reliability in predicting survival of ESCC patients.¹⁹⁸ Tian et al. identified 14 MRGs with significant prognostic value by analyzing the tumor and normal samples sourced from TCGA datasets, and 153 ESCA patients from the TCGA cohort were divided into two clusters based on the expression profile of these 14 MRGs. The results showed that the prognosis of cluster 1 was significantly better than that of cluster 2.¹⁹⁹ Together, these bioinformatic analysis displayed the potential role of mitophagy in the prognosis of esophageal cancer.

Some researchers found out that mitophagy could promote the progression of esophageal cancer. CD44 expression is associated with enhanced malignant potential in ESCC. Whelan et al. reported that the CD44-low esophageal keratinocytes would give rise to the CD44-high esophageal keratinocytes via epithelial-mesenchymal transition pathway. During the generation of CD44-high esophageal keratinocytes, the transformed cells exhibited the evidence of mitophagy, including mitochondrial fragmentation, decreased mitochondrial content, and mitochondrial translocation of Parkin. Furthermore, RNA-interference-mediated depletion of Parkin attenuates the generation of CD44-high cells. These results implicated that mitophagy could promote the progression of ESCC and be associated with poor survival of ESCC patient by involving in the generation of CD44-high esophageal keratinocytes.²⁰⁰ Yamashita et al. recruited 217 ESCC patients, including 159 patients undergoing neoadjuvant chemotherapy, and analyzed the tissue samples by immunohistochemistry to investigate the relationship between PINK1 expression and various clinicopathological factors. They found that the PINK1 expression in patients undergoing chemotherapy is significantly higher than that in patients who did not. Besides that, the higher PINK1 expression is significantly associated with the poor response to chemotherapy, and high PINK1expression is mainly associated with the poor survival of patients undergoing preoperative chemotherapy. In vitro, suppressing the expression of PINK1 by using siPINK1 could inhibit mitophagy, thereby restoring chemosensitivity of ESCC cell lines.²⁰¹

Different from the results mentioned above, some researchers reported that mitophagy could inhibit the development of esophageal cancer. RECQL4 is a member of the RECQ helicase family and takes part in several processes such as DNA double-strand break repair.²⁰² It was reported that RECQL4 is highly expressed in esophageal cancer tissues and cells and promotes the metastasis of esophageal cancer cells. Mechanistically, transcription factor CREB1 could transcriptionally activate the expression of RECQL4, while the elevated RECQL4 promoting the progression and metastasis of esophageal cancers by inhibiting mitophagy.²⁰³

In conclusion, mitophagy could exert dual effect during initiation and progression of esophageal cancer. The influence of mitophagy on the drug resistance of esophageal cancer patients remains unclear. Further research is needed to clarify the role of mitophagy in esophageal cancer (Figure 7).

Figure 7.

Mitophagy and esophageal cancer

Mitophagy could exert dual effect during initiation and progression of esophageal cancer. However, the specific role of mitophagy in esophageal cancer still remains unknown, and more studies are needed.

Liver cancer

Liver cancer is the third leading cause of cancer death after lung and colorectum cancer and the sixth most frequently diagnosed cancer, with an estimated 865,000 new cases and 757,948 deaths in 2022. Specifically, hepatocellular carcinoma (HCC) makes up 90% of primary liver cancer diagnoses.^118,204,205 Primary liver cancer comprises mainly hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Although hepatitis-induced liver cancer has been decreased due to the economic development and the popularization of hepatitis vaccine, the incidence of liver cancer developed by obesity and alcohol assumption has been increased. Since liver cancer patients have often been diagnosed with advanced cancer and drug resistance often occurs during the treatment, it is important to further investigate the underlined mechanism, develop effective treatment strategy, and overcome drug resistance. Mitophagy has attracted extensive attention for its role in the occurrence, development, and drug resistance of liver cancer.

Mitophagy exerts dual role in liver cancer

Several researches reported that mitophagy could inhibit the progression of liver cancer. IL-1α is a potent inflammatory cytokine that is released by cell necrosis, and researchers found that the level of IL-1α in monocytes in peritumoral region is significantly elevated compared with tumor region and non-tumor region. Mechanistically, IL-1α could bound to mitochondria to inhibit mitophagy via regulating mitochondrial ROS-HIF-1α pathway, thereby exerting pro-tumor effect. These results suggest that mitophagy may exert anti-tumor effect in HCC.²⁰⁶ Regulation of tumor immunity plays an important role in tumor initiation and progression. It was found that in Parkin−/− mice, the number of cytotoxic CD8⁺ T cells decreased and the number of exhausted CD8⁺ T cells increased, indicating the immune suppressive microenvironment caused by Parkin deficiency in HCC and the potential anti-tumor effect of mitophagy.²⁰⁷ Apoptin, a proline-rich VP3 structural protein of chicken anemia virus, has been found to induce apoptosis in various types of cancer but not in normal cells.²⁰⁸ Li et al. found that upregulating apoptin could increase the level of ROS and then lead to the loss of mitochondrial transmembrane potential. These could cause the initiation of mitophagy by recruiting NIX, thereby promoting apoptosis in liver cancer cells.²⁰⁹ FUNDC1, an important receptor involved in mitophagy, also participates in the regulation of HCC initiation and progression. Li et al. reported that FUNDC1 deficiency could increase the release of cytosolic mitochondrial DNA and caspase-1 activation, resulting in elevated release of proinflammatory cytokines and hyperproliferation of hepatocytes.²¹⁰

However, some researchers found that mitophagy could promote the development of liver cancer. Researchers found that overexpression of PINT87aa, a peptide encoded by the circular form of the long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT),²¹¹ could inhibit HCC cell proliferation and induce HCC cellular senescence in vitro and in vivo. Mechanistically, PINT87aa could bound to Forkhead box M1 (FOXM1) and inhibit the function of FOXM1, which could decrease the expression of PHB2 and suppress PHB2-mediated mitophagy, thereby exerting the pro-senescence role in HCC.²¹² Luo et al. reported that adenosine deaminase acting on RNA 1 (ADAR1) could dictate the transcript of GLI1, a central effector of Sonic Hedgehog signaling, through editing-dependent mechanism. They further uncovered that GLI1 editing could activate PINK1/Parkin-dependent mitophagy to ensure the few but the requisite number of functional mitochondria, which could maintain the homeostasis of liver CSCs and promote adaptive responses to targeted therapy.²¹³ Another research reported that when mitophagy is inhibited, p53 is phosphorylated and translocated into the nucleus, where it binds to the NANOG promoter and inhibits the expression of NANOG, a transcription factor critical for maintaining the stemness and the self-renewal ability of CSCs, leading to the reduction of CSC populations.²¹⁴ Ferredoxin 1 (FDX1) is a small iron-sulfur protein responsible for electron transfer and is involved in several metabolism such as bile acid metabolism.²¹⁵ It was found that FDX1 expression is significantly downregulated in HCC tissue and decreased FDX1 expression promotes HCC progression. Mechanistically, FDX1 deficiency increases the level of ROS, activating mitophagy in HCC cells and thus exerting pro-tumor effect.²¹⁶ Kim et al. reported that upon extracellular glucose repletion following depletion, transmembrane 4 L six family member 5 (TM4SF5), a member of the tetraspan(in)s family, becomes enriched in mitochondria-lysosome contact sites (MLCSs). Furthermore, Drp1 and some mitophagy receptors accumulated in these TM4SF5-enriched MLCSs, resulting in mitochondrial fission and mitophagy, which are associated with liver malignancy.²¹⁷ Researchers performed RNA-protein interactome profiling to identify potential non-canonical RBPs in HCC cells, and phosphoglycerate dehydrogenase (PHGDH) has been identified as a functional RBP. They demonstrated that PHGDH could directly bound to the 3’ untranslated region (3′ UTR) of protein kinase C delta type (PRKCD) mRNA via its RNA-binding domain, thereby stabilizing the transcript and elevating the level of PRKCD protein. The PHGDH-dependent PRKCD upregulation could promote the HCC progression by inducing mitophagy and inhibiting apoptosis.²¹⁸ Radiofrequency thermal ablation (RFA) has been applied in treatment of HCC while various factors such as tumor heterogeneity could cause incomplete RAF. HCC cells located in the incomplete RFA region are exposed to sublethal hyperthermia, and some of these HCC could recover from this reversible injury, resulting in HCC recurrence.²¹⁹ Peng et al. found that under the condition of sublethal hyperthermia, upregulated NOX4 expression in the mitochondria could trigger the production of mitochondrial ROS. The increased mitochondrial ROS could initiate PINK1-dependent mitophagy to eliminate the dysfunctional mitochondria, protecting HCC cells from cellular apoptosis.²²⁰ The RAB-interacting factor (RABIF) is a putative guanine nucleotide exchange factor,²²¹ and Feng et al. found that RABIF is upregulated in HCC correlating with poor prognosis of HCC patients. They further demonstrated that knockdown of RABIF could attenuate the PARL-PGAM5 axis-mediated mitophagy, resulting in the diminished mitochondrial ROS and decrease in basic glycolysis.²²² Stomatin-like protein 2 (STOML2), identified as an inner mitochondrial membrane protein in human erythrocytes and many other tissues, has been found to be overexpressed in HCC tissues and is associated with poor overall survival. The researchers further demonstrated that STOML2 could interact with PINK1 and stabilize PINK1, thereby enhancing the PINK1-Parkin-dependent mitophagy, thereby promoting progression and metastasis of HCC.²²³ Thioredoxin-related transmembrane protein 2 (TMX2), a membrane protein of the protein disulfide isomerase family, has been found to promote HCC proliferation, and its overexpression of TMX2 is associated with poor prognosis of HCC patients. Mechanistically, TMX2 could interact with VDAC to inhibit the formation of VDAC oligomers and recruit Parkin to dysfunctional mitochondria, thereby promoting the mitophagy and exerting pro-tumor effect in HCC.²²⁴ Intrahepatic cholangiocarcinoma (ICC) refers to a highly invasive hepatobiliary neoplasm arising in the intrahepatic biliary tree. Chen et al. reported that p62 is significantly highly expressed in ICC tissue and is positively related to poor prognosis of ICC patients. Mechanistically, highly expressed p62 could activate mitophagy to further induce EMT, thereby promoting the progression of ICC in vitro and in vivo.²²⁵

In conclusion, mitophagy exerts dual effect on the occurrence and development of liver cancer. More investigations are needed to underline the mechanism about how mitophagy influences the prognosis of liver cancer patients, especially the intrahepatic cholangiocarcinoma patients.

Mitophagy could affect the efficacy of liver cancer treatment

Sorafenib, a multi-target kinase inhibitor used as first-line therapy for advanced HCC, shows a favorable anti-tumor effect, while resistance prevents patients from benefiting from it.²²⁶ Ma et al. investigate the relationship between AFAP1L2, an adaptor protein playing a critical role in the regulation of cell proliferation and invasion, and artesunate derived from Artemisinin. They found that AFAP1L2 is overexpressed in sorafenib-resistant HCC cells and activates the downstream Src-FUNDC1 pathway, thus preventing the FUNDC1 recruitment to mitochondria and inhibiting mitophagy. Artesunate, a semi-synthetic water-soluble artemisinin derivative used as the first-line drug for malaria treatment, could suppress the expression of AFAP1L2 in sorafenib-resistance cells and inhibit the phosphorylation of FUNDC1 at the Tyr 18 site by SRC, which promotes the FUNDC1 recruitment to mitochondria and thus initiates the mitophagy and subsequent cellular apoptosis.²²⁷ Zhou et al. reported that in sorafenib-resistance HCC cells, the expression of BNIP3 and BNIP3L decreases and their levels are negatively associated with sorafenib resistance. They strikingly found that human menstrual-blood-derived stem cells could upregulate the expression of BNIP3 and BNIP3L in sorafenib-resistant HCC cells by tet methylcytosine dioxygenase 2 (TET2)-mediated active demethylations, resulting in the activation of mitophagy and subsequent autophagic cell death of sorafenib-resistant HCC cells.²²⁸ It was found that under hypoxia condition, miR-210-5p is upregulated and subsequently cause the suppression of AAA domain containing 3A (ATAD3A) protein. The suppression of ATAD3A could significantly upregulate the expression of PINK1 and Parkin and thus activate the mitophagy, leading to the survival of sorafenib-resistant HCC cells.²²⁹ Zhou et al. also found that combination of glucose-restriction and sorafenib could synergistically abolish ATP generation and mitophagy, resulting in a high cell death rate of HCC.²³⁰

Lenvatinib, another multi-kinase inhibitor used as first-line targeted therapy for advanced HCC, exhibits a prolonged overall survival for a small number of advanced HCC patients, while most patients have poor response or develop resistance during the lenvatinib treatment.²³¹ Cell competition, a vital selection and quality control mechanism, has been reported to be involved in tumorigenesis and development.²³² Wang et al. found that in lenvatinib-resistant HCC cells, overactivation of BNIP3-mediated mitophagy could switch the energy production from mitochondrial OXPHOS to glycolysis by regulating AMP-activated protein kinase (AMPK)-enolase 2 (ENO2) signaling, thereby promoting glycolysis flux and thus perpetually maintaining competitive advantage of lenvatinib-resistant HCC cells over sensitive HCC cells.²³³ It was reported that bezafibrate, a clinically approved PPARα/γ dual agonist, could activate the expression of PPARα to upregulate the carnitine palmitoyltransferase IA (CPT1A)/acyl-CoA oxidase 1 (ACOX1), which could cause fatty acid oxidation (FAO)-dependent ROS accumulation to trigger PINK1/Parkin-mediated mitophagy, thus exerting potent anti-tumor effect for HCC in vitro. Bezafibrate treatment could complement the therapeutic effect of lenvatinib, providing a promising strategy to address lenvatinib resistance.²³⁴ Yan et al. revealed that lenvatinib may initiate cytoprotective mitophagy, and knockdown of family with sequence similarity 111 member B (FAM111B) could significantly impair lenvatinib-induced mitophagy to sensitize HCC to lenvatinib.²³⁵ Researchers found that LINC01607, a competing endogenous RNA, initiates the protective mitophagy by upregulating p62, resulting in decreased ROS levels and promotion of drug resistance to lenvatinib. They also revealed that silence of LINC01607 combined with lenvatinib could reverse drug resistance and enhance the efficacy.²³⁶

The activation of the c-MET pathway is a common mechanism of resistance in cancer treatment, and cabozantinib has been reported to prolong the overall survival of patients with previously treated advanced hepatocellular carcinoma.²³⁷ Yang et al. revealed that cabozantinib could induce the expression of c-Myc and thus significantly enhance mitochondrial fragmentation and p62 aggregation, leading to promotion of mitophagy. They further demonstrated that mitophagy could eliminate the damaged mitochondria, resulting in resistance of HCC cell to cabozantinib.²³⁸

Mitophagy could also influence the treatment efficacy of chemotherapeutic drugs on HCC. Cisplatin is a basic chemotherapeutic drug, while its application in treatment for HCC patients is limited because of its low sensitivity to HCC. Sheng et al. investigated that cisplatin could activate mitophagy and lysosomal biogenesis, leading to crosstalk between mitochondria and lysosome and cisplatin resistance in HCC cells. They also found that cisplatin combined with PI3K/mTOR inhibitor could significantly enhance the sensitivity of HCC cells to cisplatin.²³⁹ 5-FU is a classical chemotherapeutic drug that is extensively used in treatment of several solid tumors. However, the resistance of 5-FU impedes its application in HCC. Salidroside, the most effective physiologically active substance in Rhodiola rosea extracts, has been reported that it could potentiate the treatment efficacy of 5-FU on HCC.²⁴⁰

Radiotherapy is also an important part of HCC treatments while local recurrence remains the main problem of radiotherapy for HCC patients. Tsuchiya et al. reported that the long noncoding RNA, nuclear paraspeckle assembly transcript 1 (NEAT1) variant 1 (NEAT1v1), could confer radioresistance to HCC by enhancing PINK1/Parkin-mediated mitophagy.²⁴¹

Taken together, these results revealed that mitophagy could affect the efficacy of liver cancer treatment. How to regulate mitophagy to improve the efficacy of liver cancer treatment and overcome drug resistance still deserves in-depth study.

Therapeutic approaches for liver cancer involving mitophagy

Researchers proposed several therapeutic strategies involving mitophagy. Tian et al. reported that they designed a cascaded copper-based metal-organic framework (MOF) therapeutic nanocatalyst by integrating cyclooxygenase-2 (COX-2) inhibitor meloxicam and chemotherapeutic agent sorafenib. This nanocatalyst could downregulate the expression of COX-2 to induce PINK1/Parkin-mediated mitophagy, which could act synergistically with sorafenib-mediated chemotherapy, thus potentiating the efficacy of sorafenib.²⁴² Park et al. synthesized spindle-shaped iron oxide nanoparticles to convert external magnetic fields into physical stress. These nanoparticles could promote mitophagy to enhance the cellular apoptosis in HCC cells.²⁴³ Li et al. also synthesized the [Cu(ttpy-tpp)Br₂] Br (CTB), a mitochondrion-targeting copper (II) complex. They further demonstrated that CTB could activate mitophagy and thus result in energy shortage, leading to HCC cellular death.²⁴⁴

Compounds derived from natural plant and traditional Chinese medicine and some existing drugs have been demonstrated to exert anti-tumor effect by regulating mitophagy. Wang et al. found that cepharanthine hydrochloride, a semi-synthetic derivative of cepharanthine, could bound to GPR30 receptors to activate the signaling cascade involving mitochondrial fission, which promotes the activation of mitophagy and thus limits the efficacy of cepharanthine hydrochloride treatment alone. Treatment of cepharanthine hydrochloride combined with autophagy inhibitors could significantly enhance the anti-tumor effect of cepharanthine hydrochloride.²⁴⁵ Icaritin is a prenylflavonoid derivative from Epimedium genus and exerts anti-tumor effect on various cancers. Researchers found that inhibition of PINK1/Parkin-dependent mitophagy promotes cell death induced by icaritin in HCC cells.²⁴⁶ Another research found that combination treatment of icaritin and doxorubicin with a molar ratio of 1:2 could synergistically induce immunogenic cell death and remodel the tumor microenvironment in HCC.²⁴⁷ Ketoconazole, a traditional antifungal agent, has been found that it could downregulate the expression of COX-2, which could cause the PINK1 accumulation and subsequent translocation of Parkin to mitochondria, promoting mitophagy and mitophagy-mediated mitochondrial dysfunction and thereby exerting anti-tumor effect.²⁴⁸ It was reported that Platycodin D2 (PD2), a new saponin compound extracted from the traditional Chinese medicine Platycodon grandiflorum, could significantly inhibit the proliferation of HCC cells and promote cell senescence. Mechanistically, PD2 could upregulate the expression of NIX and subsequently induce NIX-dependent mitophagy, leading to activation of P21/CyclinA2 pathway and promotion of cell senescence.²⁴⁹ Ailanthone, a primary quassinoid derived from the traditional Chinese medicinal herb Ailanthus altissima, has been reported to inhibit PINK1/Parkin-dependent mitophagy to promote the formation of mitochondrial pores, which could activate the inflammatory response of HCC cells and ultimately suppress HCC proliferation.²⁵⁰ Polygalacin D, one of the biological active compounds isolated from Platycodon grandiflorum, has been found to significantly suppress the proliferation of HCC cells via inducing BNIP3L-dependent mitophagy.²⁵¹ Feng et al. found that resveratrol could significantly inhibit the proliferation of HCC cells in vitro and suppress the tumor growth of HCC in vivo. They further demonstrated that resveratrol promotes mitophagy to exert inhibitory effect on HCC by targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/miR-143-3p/ribonucleoside reductase M2 (RRM2) axis.²⁵² Sanguinarine, a benzophenanthridine alkaloid isolated from the root of Sanguinaria canadensis, has been found to induce ROS-mediated mitophagy, which significantly inhibits the growth of HCC.²⁵³ Reuterin is the major metabolite of Lactobacillus reuteri (L. reuteri) and has been found to exert great anti-HCC potential. Researchers found that reuterin treatment could impair mitophagy and cause the aberrant aggregation of mitochondrial nucleoids to block mtDNA replication and mitochondrial fission, thereby promoting the leak of mtDNA and the subsequent activation of STING pathway.²⁵⁴ Researchers found that leukemia inhibitory factor (LIF) could promote HCC proliferation and metastasis. They further showed that biotin-modified cyclovirobuxine D (CVB-D) probe could bind to LIF at Valine 145 site and then induce mitophagy by activating the p38MAPK/p62 pathway to inhibit HCC migration and metastasis.²⁵⁵

In summary, these results suggest that therapeutic strategies by regulating mitophagy could be a potential approach for liver cancer treatment and warrant further investigations (Figure 8).

Figure 8.

Mitophagy and liver cancer

Mitophagy exerts dual role in liver cancer and influences the efficacy of liver cancer treatment. Therapeutic strategies for liver cancer patients by regulating mitophagy need further investigations.

Pancreatic cancer

There were 511,000 new cases of pancreatic cancer and 467,000 deaths in 2022 reported by GLOBOCAN 2022. The disease is among the poorest in terms of prognosis and many patients are diagnosed with advanced cancer.^118,256 In addition, there are several problems during the treatment for pancreatic cancer patients such as drug resistance and poor response to treatment. It is urgent to elucidate the mechanism of cancer initiation and development and overcome the drug resistance, thus prolonging the overall survival of pancreatic cancer patients. Mitophagy, a part of mitochondrial quality control mechanism, has attracted extensive attention about its role in pancreatic cancer. Aashrafizadeh et al. reported that by applying bioinformatic analysis, mitophagy was found to be dysregulated in pancreatic cancer, and the dysregulated mitophagy could enhance the proliferation of pancreatic cancer cells.²⁵⁷ Zhuo et al. identified three mitophagy-related genes from the TCGA cohort, and a three-gene prognostic model was established and validated in different cohorts. According to the prognostic model, the pancreatic cancer patients were divided into high-risk group and low-risk group. Patients in high-risk group have worse overall survival than that of patients in low-risk group, while patients in high-risk were more sensitive to paclitaxel and erlotinib.²⁵⁸ Chen et al. reported that three distinct mitophagy subtypes (low, high, and intermediate) of pancreatic cancer were identified based on various bioinformatics tools and database. They found that pancreatic cancer with a high mitophagy subtype had the worst prognosis and was insensitive to erlotinib, sunitinib, and imatinib compared to other mitophagy subtypes, which revealed that mitophagy is significantly involved in pancreatic cancer progression and treatment resistance.²⁵⁹ Besides the results above, mitophagy has been widely demonstrated to be involved in the occurrence, development, and drug resistance of pancreatic cancer.

Mitophagy is involved in the occurrence and progression of pancreatic cancer

A large number of studies have shown that mitophagy could inhibit the development of pancreatic cancer. Lidamycin is a macromolecular enediyne antibiotic, and it has been found that lidamycin could exert suppression of pancreatic cancer cells. Mechanistically, lidamycin upregulates the expression of MFN2 while knockdown of the MFN2 expression could weaken the BNIP3L-dependent mitophagy in pancreatic cancer, which attenuates the inhibitory effect of lidamycin on pancreatic cancer cells. These results suggest that lidamycin might suppress the proliferation and progression of pancreatic cancer cell by promoting mitophagy.²⁶⁰ UGT8 is involved in sulfatide biosynthesis, and Chen et al. found that after suppressing the expression of UGT8, mitophagy was activated which inhibit the tumor growth in vivo.²⁶¹ It was reported that myoferlin is overexpressed in several cancers including pancreatic cancer, and WJ460 is a small molecular inhibition targeting myoferlin. Rademaker et al. reported that WJ460 could trigger mitophagy and ROS accumulation in pancreatic cancer cells, causing lipid peroxidation and cell death, suggesting mitophagy could exert anti-cancer effect in pancreatic cancer.²⁶² Li et al. reported that the depletion of PINK1 and Parkin accelerate the oncogenic Kras-driven pancreatic tumorigenesis. They further demonstrated that PINK1/Parkin deficiency could promote the mitochondrial iron accumulation and that the overload of mitochondrial iron could contribute to the Warburg effect in pancreatic cancer cells.²⁶³ PPARγ was upregulated in pancreatic cancer cells. Nie et al. found that PPARγ is positively related to poor prognosis of pancreatic cancer patients. In vitro and in vivo assays demonstrated that PPARγ could increase the expression of superoxide dismutase 2 (SOD2) to inhibit mitophagy, reducing mitochondrial ROS-dependent apoptosis and promoting proliferation of pancreatic cancer cells.²⁶⁴

However, several investigations demonstrated that mitophagy could promote the progression of pancreatic cancer. Cancer-associated fibroblasts (CAFs) are one of the most critical stromal cells that play important role in promoting tumor growth, metastasis, and treatment resistance. It was reported that mitophagy could modulate the proline synthesis to promote collagen secretion, thereby maintaining the phenotype of CAFs and promoting the growth of tumor in vivo.²⁶⁵ Jia et al. found that fisetin, a natural flavonoid, inhibits proliferation of pancreatic cancer cells and the growth of tumor in vivo and promotes PINK1/Parkin-dependent mitophagy in an AMPK-dependent manner. However, combination treatment with fisetin and autophagy inhibitor such as 3-methyladenine (3-MA) resulted in decreased cell viability (18%) compared with the cell viability (49%) in the group treated with fisetin alone, suggesting that mitophagy might exert cytoprotective role in pancreatic cancer cells treated with fisetin.²⁶⁶ Ubiquitin-like (UbL) modifiers such as SUMO play an important role in cancer progression and mitochondrial dynamics. Researchers have also investigated the role of another UbL modifier, interferon-stimulated gene 15 (ISG15), in the progression and metabolic plasticity of pancreatic cancer. They found that ISG15, specifically its post-translational modification process known as ISGylation, is upregulated in pancreatic cancer stem cells (PaCSCs) and plays an important role in maintaining metabolic plasticity and renewal of PaCSCs by promoting mitophagy.²⁶⁷ KRAS mutation is often associated with the cancer progression and metastasis, and KRAS ^G12D is one of the types of KRAS mutation. It was reported that overexpression of KRAS ^G12D could increase the mRNA expression of BNIP3L/NIX, and the sustained Kras signaling is essential for maintenance of NIX level. Furthermore, the NIX-depleted KC mice reserved a significantly larger fraction of disease-free pancreas tissues than the control group, proving the delay of pancreatic intraepithelial neoplasia progression (PanIN). These results suggest that NIX-dependent mitophagy might promote the progression of K KRAS^G12D-driven PanIN to pancreatic cancer.²⁶⁸ Dysregulation of SMAD4 is strongly associated with poor pancreatic cancer prognosis,²⁶⁹ and it was found that SMAD4 deficiency could induce pancreatic cancer cells resistant to inhibitors of the ETC by increasing mitophagic flux mediated by elevated MARK/ERK signaling.²⁷⁰

Altogether, these results revealed that mitophagy is closely associated with the occurrence and development of pancreatic cancer. The inconsistence results between different studies suggest that the underlined mechanism about how mitophagy regulates the progression of pancreatic cancer still remains unclear, and further investigations are needed.

Mitophagy plays a crucial role in the development of drug resistance

Gemcitabine is the first-line chemotherapeutic drug for pancreatic cancer patients and the development of drug resistance attenuates the efficacy of gemcitabine. Masuo reported that after the acquisition of gemcitabine resistance, the mitochondrial number increased in resistance cell lines, accompanied with decreased mitochondrial fission 1 protein, which induces mitochondrial fission, thus promoting mitophagy. These results suggest that mitophagy might be involved in the development of gemcitabine resistance in pancreatic cancer cells.²⁷¹ Ivermectin is an antiparasitic drug, and it was reported that ivermectin-gemcitabine combination treatment could synergistically inhibit mitophagy to induce apoptosis, thus inhibiting tumor growth in vivo.²⁷² Kim et al. identified that sodium/myo-inositol co-transporter solute carrier family 5 member 3 (SLC5A3) is the key modulator promoting chemoresistance in pancreatic cancer and that SLC5A3 is significantly upregulated in gemcitabine-resistance pancreatic cancer cells. They found that suppressing the expression of SLC5A3 could activate the PINK1/Parkin-dependent mitophagy, leading to excessive elimination of mitochondria and thus sensitize pancreatic cancer cells to gemcitabine treatment.²⁷³ STOML2 is located in the mitochondrial inner membrane and is responsible for maintaining the stability of mitochondria.²⁷⁴ Researchers found that the patients with higher level of STOML2 have better survival, and elevated STOML2 could inhibit the proliferation and chemotherapy resistance of pancreatic cancer cells. Mechanistically, STOML2 could directly bind to and stabilize PARL, thereby suppressing PINK1/Parkin-dependent mitophagy and repressing chemoresistance in pancreatic cancer cells.²⁷⁵

In conclusion, these results demonstrated that mitophagy could affect the development of drug resistance of pancreatic cancer patients. Regulating mitophagy could be a promising approach to overcome drug resistance of pancreatic cancer patients.

Mitophagy-targeted approach could enhance the efficacy of pancreatic cancer treatment

6-Methoxydihydroavicine (6-ME), an alkaloid extracted from M. cordata, was reported to induce cell death of pancreatic cancer cells. Mechanistically, 6-ME could disrupt the oxaloacetic acid (OAA) metabolism to increase ROS production, which could promote mitophagy, ultimately contributing to anti-tumor effect in pancreatic cancer cells.²⁷⁶ Cucurbitacin B (CuB) is an active component in plants of the Cucurbitaceae family, and it was reported that CuB could activate PINK1/Parkin-dependent mitophagy by inhibiting the PI3K/Akt/mTOR pathway, which could inhibit cancer cell proliferation, migration, and invasion, thereby inhibiting the progression of pancreatic cancer.²⁷⁷ Dichloroacetate (DCA) is a drug known to divert metabolism from anaerobic glycolysis to mitochondrial oxidative phosphorylation. After treated with DCA, two pancreatic cancer cell lines, PANC-1 and BXPC-3, showed decreased cell proliferation and migration. Furthermore, DCA treatment could also increase the content of mtDNA and mitophagy marker LCB3-II in both cell lines, suggesting that DCA might exert anti-tumor effect involving mitophagy.²⁷⁸ Kshattry et al. reported that cyst(e)inase, an engineered human enzyme, in combination with auranofin, a thioredoxin reductase inhibitor, could synergistically increase mitochondrial ROS and inhibit mitophagy, contributing to suppression of proliferation and survival of pancreatic cancer cells.²⁷⁹ Wang et al. reported that the miriplatin (MPt)-loaded liposome, LMPt, exhibits totally different anticancer mechanism from previously used platinum agents. This LMPt could be released and targeted to mitochondria, thus enhancing the binding of mitochondrial protease LONP1 with POLG and TFAM to degrade POLG and TFAM. Then, POLG and TFAM degradation initiated mtDNA replication blocking, inducing mitophagy via PINK1-Parkin axis, ultimately suppressing the progression of pancreatic cancer cells.²⁸⁰ Rocaglamide A (Roc-A) is a bioactive molecule extracted from the plant Aglaia elliptifolia that has been identified as a therapeutic choice for several types of cancer. Zhao et al. reported that Roc-A could trigger mitophagy via PINK1/Parkin-dependent pathway while inhibition of mitophagy could make pancreatic cancer cells more sensitive to Roc-A.²⁸¹

Taken together, these results suggest that mitophagy-targeted treatment could be a potential therapeutic strategy to enhance the efficacy of pancreatic cancer patients and a supplement of traditional treatment (Figure 9).

Figure 9.

Mitophagy and pancreatic cancer

Mitophagy is significantly associated with the occurrence and progression of pancreatic cancer and influence the development of drug resistance of pancreatic cancer patients. Mitophagy-targeted treatment could be a potential therapeutic strategy and a supplement of traditional treatment for pancreatic cancer patients.

Discussion

Digestive system cancer is the great burden for public health, and it is urgent to develop more efficient therapeutic strategies. In recent years, more and more investigations have focused on the regulatory mechanism of mitophagy and its role in digestive system cancer, providing further insights for the development of therapeutic strategies. Different from digestive system cancer, some key proteins of mitophagy show more clear biological roles in other tumors such as breast cancer. For example, high Parkin expression is associated with better histological grade and prognosis in breast cancer and could also enhance the sensitivity of breast cancer patients to paclitaxel treatment.^282,283,284 High expression of FUNDC1 is associated with poor prognosis of breast cancer patients and could promote the proliferation and metastasis of breast cancer.^284,285,286 These results suggest that the biological roles of mitophagy may be more sophisticated in digestive system cancer.

Despite significant advances in understanding mechanism of mitophagy and the role of mitophagy in regulation of digestive system cancer occurrence and progression, several critical issues constrain the translational value and broader applicability of the current findings. First, as mentioned above, mitophagy could play a dual role as both tumor suppressor and promoter in regulation of cancer initiation and progression, hindering its application in clinical practice. Second, the complex interplay between mitophagy and mitochondrial dynamics and mitochondrial biogenesis remains incompletely characterized, which also makes the development of targeted therapies against mitophagy more complex and difficult. Third, although a large number of researchers have studied the role of mitophagy in digestive system tumors in detail, most of these investigations have not considered whether the role of mitophagy is different in different tumor stages or different sites in the same cancer. For example, left-sided colon cancer and right-sided colon cancer have distinct microbes and immune characterization.^287,288 With the gradual refinement and maturation of cancer molecular subtypes, the role of mitophagy in different molecular subtypes of the same type of cancer still needs to be further explored. Finally, in the process of searching the literature, we found that most of the research results on the role of mitophagy modulators come from preclinical models, which may not truly reflect the role of mitophagy modulators in the treatment of digestive system cancer. Clinical studies are still needed to prove the therapeutic efficacy of mitophagy modulators in the clinical practice.

Limitations of the study

While this review aims to provide a comprehensive insight of mitophagy, some limitations exist. Due to the possibility of publication bias, it is possible that there are missed relevant researches despite our extensive search of the literature. In addition, as a narrative review, the selection and interpretation of findings and evidence rely on academic judgment rather than rigorous systematic methodology, which could cause the subjective bias derived from authors. Nevertheless, we still hope that this review will provide researchers with more useful information and insights to promote the research progress of mitophagy in digestive system tumors.

Conclusion and future perspective

Mitophagy is an important part of mitochondrial quality control mechanism and plays a critical role in maintaining cellular homeostasis. In this review, we briefly summarize the research progress on the regulatory mechanism of mitophagy, discuss how mitochondrial biogenesis and mitochondrial dynamics influence mitophagy, and investigate the role of mitophagy in the initiation and progression of digestive system cancer. Looking forward, we suggest that the following aspects are needed to conduct further investigations, including the regulatory mechanism of mitophagy in the occurrence and development of digestive system cancer, the mechanism about how mitophagy affects the efficacy of cancer treatment, the development of mitophagy modulators, and the clinical investigations about the efficacy of mitophagy modulators on digestive system cancer patients.

Data and code availability

No new datasets, materials, or software were generated, since this work is a narrative review.

Acknowledgments

We are thankful for the support of National Natural Science Foundation of China (grant number: 82303944), the China Postdoctoral Science Foundation (grant number: 2023M731557), the Natural Science Foundation of Guangdong Province (grant number: 2025A1515012583), and the Guangdong Medical Research Foundation (grant number: B2024184). This work was supported by the National Natural Science Foundation of China (grant number: 82303944), the China Postdoctoral Science Foundation (grant number: 2023M731557), the Natural Science Foundation of Guangdong Province (grant number: 2025A1515012583), and the Guangdong Medical Research Foundation (grant numbers: B2024184). These funds have no involvement in relation to the study design; collection, analysis, and interpretation of data; writing of the report; and decision to submit the article for publication.

Author contributions

E.Q. and G.L. wrote the manuscript. G.W. and Z.L. revised and supervised the manuscript. J.H. prepared the figures. All authors read and approved the final manuscript.

Declaration of interests

The authors declare no competing interests.

Declaration of generative AI and AI-assisted technologies in the writing process

The authors declare that there was no use of generative AI and AI-assisted technologies in the writing process.