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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Mech Ageing Dev. 2020 Apr 11;188:111245. doi: 10.1016/j.mad.2020.111245

Mitophagy in Cardiovascular Homeostasis

Ruohan Zhang 1,2,3, Judith Krigman 1,2, Hongke Luo 1,2, Serra Ozgen 1, Mingchong Yang 1,2, Nuo Sun 1,2,*
PMCID: PMC7375934  NIHMSID: NIHMS1586726  PMID: 32289324

Abstract

Mitochondria are essential organelles that generate energy to fuel myocardial contraction. Accumulating evidence also suggests that, in the heart, mitochondria may contribute to specific aspects of disease progression through the regulations of specific metabolic intermediates, as well as the transcriptional and epigenetic states of cells. If damaged, the mitochondria and their related pathways are hindered, which may result in or contribute to the development of a wide range of cardiovascular diseases. Therefore, the maintenance of cardiac mitochondrial function and integrity through specific mitochondrial quality control mechanisms is critical for cardiovascular health. Mitophagy is part of the overall mitochondrial quality control process, and acts as a specialized autophagic pathway that mediates the lysosomal clearance of damaged mitochondria. In response to cardiac stress and injury, the pathways associated with mitophagy are triggered resulting in the removal of damaged mitochondrial, thereby maintaining cardiac homeostasis. In addition, recent studies have demonstrated an essential role for mitophagy in both developmental and disease-related metabolic transitioning of cardiac mitochondria. Here, we discuss the physiological and the pathological roles of mitophagy in the heart, the underlying molecular mechanisms, as well as potential therapeutic strategies based on mitophagic modulation.

Introduction

The heart has high basal energy demands and relies critically on mitochondrial oxidative phosphorylation to fuel myocardial contraction (Bertero and Maack, 2018; Murphy et al., 2016). Cardiac mitochondria make up between 23% and 32% of myocellular volume, which possess the capacity to use multiple metabolic substrates and the flexibility to switch substrate utilization under a wide range of physiological and pathological conditions (Bertero and Maack, 2018; Murphy et al., 2016; Schaper et al., 1985). In the normal adult heart, mitochondrial fatty acid β-oxidation (FAO) accounts for 60–80% of myocardial ATP production, while the remaining energy production results from glycolysis, glucose oxidation, lactate and ketones (Aubert et al., 2016; Bertero and Maack, 2018; Goldenberg et al., 2019; Sack and Kelly, 1998). Regulation of the cardiac energy metabolism is determined by energy demand, availability of substrates, activity of metabolic enzymes and oxygen content (Bertero and Maack, 2018; Murphy et al., 2016). In addition, mitochondria are essential organelles that provide a variety of cellular functions beyond energy production, such as cell death initiation, calcium storage/buffering, generation of reactive oxygen species (ROS), and modulation of inflammation (Mishra and Chan, 2016; Sun et al., 2016; Wallace et al., 2010). Another mechanism by which mitochondria might contribute to cardiovascular homeostasis is through the regulation of the Krebs cycle-derived metabolites, which play an important role in regulating the transcriptional and epigenetic states of cells. It has been increasingly clear that signaling between the nucleus and the mitochondria occurs in both directions (Martinez-Reyes and Chandel, 2020). The nuclear DNA codes for the great majority of mitochondrial proteins, and cellular bioenergetics can be perturbed by alterations in nuclear DNA expression (Murphy et al., 2016; Pagliarini et al., 2008). Similarly, in response to environmental stressors, mitochondria can stimulate a retrograde response to the nucleus and regulate the expression of different genes (Martinez-Reyes and Chandel, 2020). Recent studies also suggest metabolites generated via tricarboxylic acid (TCA) metabolism can contribute to chromatin modifications, DNA methylation, and post-translational modifications (Martinez-Reyes and Chandel, 2020; Murphy et al., 2016). It is not surprising that chromatin modifications depend largely on the mitochondrial metabolism-derived carbon intermediates (e.g., methyl, acetyl, etc.). For example, α-ketoglutarate, a Krebs cycle intermediate, is an important cofactor for the ten-eleven translocation (Tet)-dependent DNA demethylases, linking metabolism to cytosine demethylation reactions (Martinez-Reyes and Chandel, 2020; Wu and Zhang, 2014). Metabolites additionally play a critical role in the acetylation process, which represents another important set of epigenetic modifications through communication between mitochondria and the nucleus. While acetyl-CoA can function as a direct substrate of acetylation, defective mitochondria can affect acetylation process by altering acetyl-coenzyme A metabolism (Scott et al., 2014; Zhao et al., 2010). Importantly, recent findings have highlighted the role of NAD+/NADH redox state in multiple cellular metabolic processes and energy transduction, which appear to be mediated, in part, by the sirtuin family of NAD-dependent deacetylases (Lee et al., 2019; Lee et al., 2016). Therefore, in addition to participating in bioenergetics, mitochondria may serve as platforms for intracellular signaling, as well as regulators of transcriptional and epigenetic states.

Alterations in mitochondrial function have been increasingly recognized as a major contributor to a broad variety of cardiac diseases (Ardehali et al., 2012; Bravo-San Pedro et al., 2017; Murphy et al., 2016). While mutations of nuclear DNA or mitochondrial DNA-encoded genes relevant to mitochondrial function could manifest as cardiomyopathy (Heddi et al., 1999; Koopman et al., 2012; Phoon et al., 2012; Picard et al., 2014; Wallace et al., 2010), mitochondrial dysfunction under conditions of energy deprivation, oxidative stress, defective calcium transport and impaired metabolic signaling would result in the development of cardiac pathology or susceptibility to injury (Ardehali et al., 2012; Bravo-San Pedro et al., 2017; Houten et al., 2016; Murphy et al., 2016). Therefore, it is critical to preserve cardiac mitochondrial homeostasis through balanced mitochondrial biogenesis and specific mitochondrial quality control pathways (Bravo-San Pedro et al., 2017; Saito and Sadoshima, 2015). As part of the overall mitochondrial quality control process, mitophagy mediates the identification and selectively elimination of damaged or dysfunctional mitochondria (Sun et al., 2016; Tong and Sadoshima, 2016; Youle and Narendra, 2011). Over the past decade, significant progress has been made in demonstrating the important role of mitophagy in a wide variety of cardiomyocyte functions (Billia et al., 2011; Bravo-San Pedro et al., 2017; Murphy et al., 2016; Tong and Sadoshima, 2016; Wang et al., 2018). Efficient clearance of damaged mitochondria through mitophagy plays a crucial role in maintaining myocardial metabolic homeostasis, energy production, and cardiomyocyte survival (Billia et al., 2011; Bravo-San Pedro et al., 2017; Tong and Sadoshima, 2016; Wang et al., 2018). Conversely, impaired mitophagy leads to accumulation of damaged mitochondria, contributing to the pathogenesis of various cardiovascular diseases (Kubli et al., 2013; Matsui et al., 2007; Nakai et al., 2007; Saito and Sadoshima, 2015; Zhang et al., 2017).

A decline in mitochondrial function and mitophagy has been associated with normal aging and correlated with the progression of a wide range of age-related diseases, including cardiovascular disease (Sun et al., 2016). Increasing lines of evidence have established the longevity-extending effects of enhanced mitophagy in various model organisms (Eisenberg et al., 2016; Fang et al., 2019; Ren and Zhang, 2018). Interestingly, recent studies suggest that augmented mitophagy may be able to counteract aging-associated cardiac dysfunction (Eisenberg et al., 2016). Consequently, there is great interest in investigating the mitochondrial quality control pathways, as they potentially could provide novel therapeutic approaches for cardiac aging and other aging-associated diseases. In this review, we will provide insight into the role of mitophagy in normal cardiovascular physiology and in pathological circumstances. We will review how modulation of different aspects of cardiac mitophagy in murine models affects cardiac function and will discuss whether mitophagy could be a potential target for novel therapeutic interventions.

Mitochondrial quality control through mitophagy

Mitophagy is a necessary mechanism to maintain mitochondrial quality by removing faulty mitochondria (Sun et al., 2015; Youle and Narendra, 2011). In the past decade, considerable progress has been made in unravelling the multiple mechanistically distinct pathways regulating mitophagy. In one of the best-characterized pathways, mitochondria targeted for mitophagic destruction appear to be molecularly marked by the ubiquitination of a host of outer mitochondrial membrane proteins (Lazarou et al., 2015; Youle and Narendra, 2011). This ubiquitination is positively regulated, in part, by the mitochondrial-targeted, PTEN-induced putative kinase 1 (PINK1), and the E3 ubiquitin ligase Parkin, known for their role in early-onset Parkinson’s disease (Lazarou et al., 2015; Narendra et al., 2009; Youle and Narendra, 2011). Under steady-state conditions, healthy mitochondria import and constitutively degrade PINK1 kinase in a mitochondrial-membrane-potential (Δψm) -dependent manner. On damaged mitochondria, however, a fall in Δψm and mitochondrial depolarization can suppress PINK1 degradation. This leads to the accumulation of PINK1 on the impaired mitochondria, phosphorylating ubiquitin attached to mitochondrial outer membrane proteins and recruiting Parkin from the cytosol to the mitochondria. Once at the mitochondrion, Parkin further ubiquitinates a number of mitochondrial proteins, thereby triggering the recruitment of receptors such as optineurin (OPTN) and NDP52 (Lazarou et al., 2015; Youle and Narendra, 2011). Therefore, ubiquitination of mitochondrial outer membrane proteins serves as a signal that is recognized by autophagy receptors, promoting autophagosomal engulfment of the damaged mitochondria (Figure 1a).

Figure 1.

Figure 1.

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The pathways of mitophagy. (a) The PINK1/Parkin dependent mitophagy: PINK1 accumulates on damaged mitochondria, phosphorylates ubiquitin attached to OMM and recruits cytosolic Parkin to the mitochondria. Activation of Parkin results in the ubiquitination of OMM proteins, which are recognized by mitophagy receptors such as optineurin (OPTN) and NDP52. These receptors bind to phagophore-located LC3 and promote autophagosomal engulfment of the damaged mitochondria. (b) Upregulated OMM proteins, BNIP3 and NIX, can directly bind to LC3 on autophagosome to facilitate autophagic engulfment of mitochondria. (c) In response to hypoxia, PGAM5 dephosphorylates FUNDC1 to initiate its interaction with LC3, enabling mitophagy.

The removal of mitochondria can also proceed in a PINK1/Parkin-independent pathway using the proapoptotic Bcl2 family proteins Nix and Bnip3 (Hanna et al., 2012; Novak et al., 2010) (Figure 1b). For instance, during programmed mitochondrial degradation in reticulocytes, upregulated BNIP3L/NIX on the outer mitochondrial membrane (OMM) facilitates direct contact with LC3 on autophagosomes and participates in autophagic engulfment of mitochondria (Hanna et al., 2012; Novak et al., 2010). Of note, genetic ablation of BNIP3L/NIX in mice prevents mitochondrial degradation during erythroid maturation (Sandoval et al., 2008). The mitochondrial outer membrane protein FUNDC1 (FUN14 domain containing 1) can also integrate with LC3 through its LC3-interacting region (LIR) and recruit autophagosome, thereby enabling mitochondrial degradation (Chen et al., 2016; Liu et al., 2012) (Figure 1c). Mitophagic actions of FUNDC1 appear to be mediated by its phosphorylation status regulated by Unc-51 Like Autophagy Activating Kinase 1 (ULK1), casein kinase 2 (CK2) or PGAM5 phosphatase (Chen et al., 2014; Chen et al., 2016; Palikaras et al., 2018). Despite the wealth of mechanistic information on the role of OMM components in mitophagy, whether inner mitochondrial membrane (IMM) proteins can function as a mitophagy receptor has not been fully understood. Recent studies indicate a crucial role for the IMM protein prohibitin 2 (PHB2) as a mitochondrial receptor for mitophagy (Wei et al., 2017). PHB2 is a component of the mitochondrial prohibitin complex that associates with LC3 upon mitochondrial depolarization (Wei et al., 2017). Interestingly, disruption of the OMM is required for the access of LC3 to PHB2, and Parkin facilitates this interaction (Wei et al., 2017).

Mitophagy is also connected to processes of mitochondrial dynamism and mitochondrial biogenesis (Palikaras et al., 2018; Pickles et al., 2018; Youle and Narendra, 2011). Mitochondrial morphology varies depending on the metabolic status and is constantly remodeling via fission and fusion (Mishra and Chan, 2016). Mitofusins, MFN1 and MFN2, are responsible for OMM fusion, whereas optic atrophy protein 1 (OPA1) promotes the subsequent IMM fusion (Mishra and Chan, 2016). In contrast, mitochondrial fission is mediated through the dynamin-related protein 1 (DRP1), a large GTPase that docks to mitochondrial fission sites by interacting with the OMM proteins such as MFF, MiD49 and MiD51 (Friedman and Nunnari, 2014; Mishra and Chan, 2014, 2016). In addition to promoting mitochondrial fusion, MFN2 can be phosphorylated by the PINK1 kinase in damaged mitochondria, and act as a Parkin substrat that facilitates both Parkin translocation and its subsequent ubiquitination of OMM proteins (Chen and Dorn, 2013). As such, a defective mitophagy is observed in mouse hearts deficient in MFN2, independent of its activity in fission/fusion regulation (Song et al., 2014). It has been suggested that mitochondrial fission may promote mitophagy. Of note, several studies have demonstrated that DRP1 plays an important role in mediating cardiac mitochondrial function and mitophagy, thereby regulating cardiac pathophysiology in response to stress (Kageyama et al., 2014; Shirakabe et al., 2016; Song et al., 2015a). The particular role for Parkin-dependent or Parkin-independent mechanism in DRP1 mediated mitophagy, however, is still under investigation (Kageyama et al., 2014; Song et al., 2015a).

In summary, the mechanisms regulating mitophagy have received increased attention during past decade. Mitophagy is essential in maintaining mitochondrial quality, and can proceed via multiple distinct mechanisms. Despite significant advancements in understanding the regulatory programs, further investigation may still be required to elucidate the precise role of mitophagy in vivo, as well as the underlying molecular mechanisms in normal physiology and in various disease states. It is worth noting that recent progress in establishing more reliable methods to monitor in vivo mitophagic flux would highly advance our understanding of the quality control mechanisms in mitochondria(Laker et al., 2014; McWilliams et al., 2016; Sun et al., 2017; Sun et al., 2015).

Mitophagy in cardiovascular homeostasis

Accumulating evidence links an intact mitophagic response to the preservation of cardiovascular mitochondrial function within a wide range of physiological and pathological conditions. The functional significance of mitophagy in cardiovascular homeostasis has been evaluated using multiple genetic approaches affecting general autophagy (like ATG5, ATG7, etc.)(Bravo-San Pedro et al., 2017; Nakai et al., 2007). While many questions remain, selective removal of damaged or dysfunctional mitochondria through mitophagy is dependent upon, in most cases, a functional macroautophagy machinery (Palikaras et al., 2018; Youle and Narendra, 2011). Mice with temporally controlled cardiomyocyte-specific deletion of ATG5 (autophagy related 5), an essential gene for optimal autophagic responses, develop left ventricular dilatation and contractile dysfunction accompanied by an accumulation of damaged mitochondria (Nakai et al., 2007; Taneike et al., 2010). Furthermore, animals with cardiac-specific deficiency of ATG5 early in cardiogenesis exhibit cardiac dysfunction one week under pressure overload (Nakai et al., 2007). In another loss-of-function mouse model of autophagy achieved by cardiac-specific ATG7 ablation, ATG7-dependent activation of cardiac mitophagy is proposed to protect the heart during to a high-fat diet consumption (Tong et al., 2019). However, this form of autophagy may not play a predominant role in mediating cardiac mitochondrial degradation in response to starvation or ischemia (Saito et al., 2019).

Extensive genetic studies have demonstrated the key metabolic sensors, AMP activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR), regulate general autophagy (Egan et al., 2011; Kim et al., 2011; Wu et al., 2013). Through phosphorylation, activation of AMPK and inhibition of mTOR can activate several proteins involved in autophagy initiation, including the Ser/Thr-kinase ULK1 (unc-51 like autophagy activating kinase), BECN1 (beclin 1), and VPS34 lipid kinase (phosphatidylinositol 3-kinase catalytic subunit type 3) (Kim et al., 2011; Russell et al., 2013). In particular, ULK1 is required for early autophagosome formation, and can translocate to mitochondria, where it phosphorylates FUNDC1, thereby regulating mitophagy (Wu et al., 2014). Of note, activation of mitophagy in response to energy stress is suggested to be mediated by ULK1-dependent mitophagy. This mechanism also plays an essential role in protecting the heart against damage following myocardial ischemia(Saito et al., 2019). The activity of ULK1 is regulated by AMPK, which is a metabolic master switch that plays a pivotal role in energy homeostasis (Kim et al., 2011; Wang et al., 2018). AMPK is a heterotrimeric protein complex composed of a catalytic subunit (AMPKα) and 2 regulatory subunits (AMPKβ and γ). The α, β, and γ subunits can also be found in isoforms (α1, α2, β1, β2, γ1, γ2, and γ3) (Wang et al., 2018). A recent study has revealed an important role of AMPKα2 in preserving cardiac function during pressure overload induced hypertrophy and heart failure, through PINK1 mediated mitophagy (Wang et al., 2018). These studies have demonstrated an essential role of autophagy/mitophagy in preventing the progression of heart failure and provide a potential therapeutic strategy by modulating the AMPK, mTOR and ULK1 regulated autophagy/mitophagy signaling pathways.

The discovery that PINK1 and Parkin interact to promote mitophagy has dramatically expanded our understanding of the mechanisms underlying mitochondrial quality control. However, whether this mechanism represents the major mechanism of mitophagy in the heart requires further investigation. In fruit flies, genetic inhibition of either PINK1 or Parkin is detrimental to mitochondrial fitness and to contractile function in the heart (Bhandari et al., 2014; Guo, 2012). However, mice with germline deletion of Parkin in mouse exhibit normal baseline cardiac function (Kubli et al., 2013; Piquereau et al., 2013). Activation of non-selective autophagy in cardiomyocytes may compensate for Parkin-mediated mitophagy mitochondrial quality, thus providing cardiomyocytes additional mechanisms to maintain mitochondrial quality. Genetic deletion of PINK1 in mice, however, evokes hypertrophy and progressive cardiac dysfunction (Billia et al., 2011). The protective effect of PINK1/Parkin mediated mitophagy in the heart appears to be more important under stress. Parkin-deficient mice exhibit an increased sensitivity to damage from myocardial infarction (MI) or cardiac aging, due to a decrease in mitophagy and accumulation of dysfunctional mitochondria (Hoshino et al., 2013; Kubli et al., 2013). Translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins have also been observed during the acute phase of MI (Kubli et al., 2013). Likewise, PINK1-deficient mice exhibit increased infarct size after ischemia-reperfusion injury (Siddall et al., 2013). Moreover, recent studies also suggest that this pathway of mitochondrial quality control could indeed be important following exhaustive exercise, which acutely stresses cardiac mitochondria (Sliter et al., 2018). Taken together, PINK1 and Parkin may sense mitochondrial damage in the heart and promote mitophagy under specific cardiac pathophysiological circumstances, which are as yet but incompletely understood.

Cell biological observations suggest that mitochondria can form highly interconnected tubular and elongated networks, a process termed mitochondrial fusion (Mishra and Chan, 2014, 2016; Rambold et al., 2011). Mitochondrial fission, on the other hand, occurs in an asymmetric manner, which allows for mitochondrial fragmentation and segregation of damaged mitochondrial components (Mishra and Chan, 2014, 2016; Rambold et al., 2011). In the heart, genetic manipulation of proteins involved in mitochondrial fission and fusion has provided considerable insight into their important role in cardiac mitophagic quality control (Ikeda et al., 2015; Shirakabe et al., 2016). Genetic deletion of DRP1 suppresses mitophagy in the mouse heart, and these mutant mice develop dilated cardiomyopathy with premature death under baseline conditions (Ikeda et al., 2015). In addition, cardiac-specific DRP1 heterozygous knockout mice exhibit increased susceptibility to ischemia/reperfusion injury (Ikeda et al., 2015). Similarly, DRP1 plays an essential role in transiently activating mitophagy in response to pressure overload, while haploinsufficiency of DRP1 in the mouse heart exacerbates the progression of mitochondrial dysfunction and heart failure under pressure overload (Shirakabe et al., 2016). Furthermore, in the murine heart, DRP1 appears to be required for Parkin-independent mitophagy in preserving cardiac function (Kageyama et al., 2014). The DRP1 mediated mitophagy is observed also in the mouse muscle, where constitutive DRP1 ablation is sufficient to induce an inhibition of mitophagy pathways (Favaro et al., 2019). On the other hand, activated mitophagy has also been reported in DRP1-deficient mouse hearts (Song et al., 2015a). Mitochondrial fusion proteins also have a role in regulating mitophagy in the heart. MFN1 and MFN2 have partially overlapping functions in promoting physical tethering between mitochondria and subsequent mitochondrial fusion (Mishra and Chan, 2014, 2016; Rambold et al., 2011). On damaged mitochondria, the phosphorylation of MFN2 by the PINK1 kinase facilitates Parkin translocation to the damaged mitochondria and its subsequent ubiquitination of mitochondrial proteins (Chen and Dorn, 2013). Therefore, ablation of MFN2 in murine cardiomyocytes suppresses Parkin mediated mitochondrial quality control (Chen and Dorn, 2013). Of note, the MFN2 mutant lacking the PINK1 phosphorylation sites inhibits mitophagy, and prevents developmental metabolic transition during the perinatal period, resulting in heart failure (Gong et al., 2015). Combined ablation of both MFN1 and MFN2 in the adult mouse heart evokes lethal dilated cardiomyopathy (Papanicolaou et al., 2012; Song et al., 2015b). Another study, however, has demonstrated cardiac-specific ablation of both MFN1 and MFN2 can protect against acute myocardial infarction (Hall et al., 2016). These findings suggest that loss of MFN1 and MFN2 might be either protective or detrimental during acute or chronic cardiac stress. Surprisingly, cardiomyocyte specific deletion of both MFN1 and MFN2 provokes an accumulation of defective mitochondria without appropriately increasing mitophagy (Song et al., 2015b). Interestingly, early lethality of the DRP1 cardiac knockout mice could be delayed by an additional gene ablation of both MFN1 and MFN2 (Song et al., 2017). However, the triple knockout mice (DRP1, MFN1, MFN2) exhibit impaired mitophagy and ultimately develop myocardial hypertrophy with cardiac failure (Song et al., 2017). Collectively, whether mitochondrial fission/fusion directly affects mitophagy, and the underlying molecular mechanisms by which fission/fusion proteins mediate mitophagy in healthy and in diseased hearts merit further investigation. It is possible multiple mechanisms mediate cardiac mitophagy associated with mitochondrial fission/fusion proteins, and how PINK1-Parkin participate in the regulatory mechanisms is just beginning to be investigated.

Perspectives and targeting mitophagy as a therapeutic strategy

Cardiovascular disease (CVD) imposes an enormous medical and economic burden worldwide, and its prevalence continues to rise over time with the progressive aging of the general population (Benjamin et al., 2019; Dokainish et al., 2017). Strong evidence indicates that a decline in mitophagy may contribute to the age-related accumulation of dysfunctional mitochondria in the heart (Eisenberg et al., 2016; Inuzuka et al., 2009; Ren et al., 2017; Wang et al., 2019). Interestingly, genetic and pharmacological interventions that promote mitophagy can lead to extended life span in various model organisms (Ryu et al., 2016; Schiavi et al., 2015). For instance, overexpression of Parkin modulates the mitochondrial fission/fusion machinery and mediates the turnover of dysfunctional mitochondria, slowing the aging process in Drosophila (Rana et al., 2013). Urolithin A, a natural compound that induces mitophagy, has been identified to prolong the lifespan of C. elegans as well as to improve muscle function in rodents (Ryu et al., 2016). In aged hearts, overexpression of Parkin ameliorates the cardiac functional decline with more mitochondria incorporated into autophagosomes (Hoshino et al., 2013). Moreover, the natural polyamine spermidine can enhance cardiac mitophagy and mitochondrial respiration, thereby preserving diastolic function in older mice (Eisenberg et al., 2016). The cardioprotective effects of spermidine require the autophagy-related protein ATG5 in cardiomyocytes (Eisenberg et al., 2016). In humans, high levels of dietary spermidine correlate with a lower incidence of CVD (Eisenberg et al., 2016).

Despite our increased knowledge regarding the pathophysiology of CVD, existing medical therapeutic approaches are still limited and CVD mortality rates remain high (Benjamin et al., 2019; Dokainish et al., 2017). Maintenance of a healthy mitochondrial network may serve as an attractive therapeutic approach in the treatment of CVD (Bertero and Maack, 2018; Murphy et al., 2016). Increasing lines of evidence link intact autophagic responses to the preservation of mitochondrial function and cardiovascular homeostasis (Bertero and Maack, 2018; Murphy et al., 2016). Therefore, nutritional and pharmacological interventions are emerging as potential candidates that might be used to stimulate general autophagy in the cardiovascular system. Inhibitors of mTOR may also represent a strategy to induce general autophagy, and to protect against myocardial ischemia, cardiac hypertrophy, and cardiac aging (Dai et al., 2014; Ranek et al., 2019; Sciarretta et al., 2012; Yan et al., 2013). Tat-Beclin 1 peptide can promote autophagy/mitophagy by mobilizing endogenous Beclin 1, and improves mitochondrial function in response to pressure overload-induced heart failure (Shirakabe et al., 2016). Additionally, histone deacetylase inhibitors may reduce myocardial infarct size during ischemia/reperfusion partially through the induction of autophagic flux (Xie et al., 2014). Altogether, accumulating evidence obtained in animal models indicate autophagy/mitophagy may serve as a potential therapeutic mode for the treatment of CVD (Figure 2). However, a major challenge is to define more efficient and specific targets in the autophagy/mitophagy pathway, considering that autophagy driven by these stimuli may also regulate other critical cellular processes.

Figure 2.

Figure 2.

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Therapeutic potential of mitophagy in cardiovascular disease. Dysfuntional or damaged mitochondria can contribute to the development of cardiovascular diseases. Manipulating autophagy/mitophagy activity may preserve cardiac mitochondrial function and serve as a cardioprotective strategy.

Autophagy is an evolutionarily conserved mechanism that ensures the proper turnover of proteins and organelles (Bravo-San Pedro et al., 2017). Distinct forms of autophagy exist, including macroautophagy, microautophagy and chaperone-mediated autophagy (Bravo-San Pedro et al., 2017; Nakai et al., 2007). In most cases, mitophagic removal of damaged or dysfunctional mitochondria relies on a functional macroautophagy machinery. However, recent evidence suggests that degradation of mitochondria could be mediated by mitochondrial-derived vesicles that directly deliver part of the mitochondria to lysosomes (McLelland et al., 2014). This process requires PINK1 and Parkin function, but appears to be independent of macroautophagy (McLelland et al., 2014). Also, mitochondria can be degraded by an alternative autophagy pathway that is independent of the normal autophagic machinery (Nishida et al., 2009). Several distinct forms of mitophagy may contribute to the lysosomal engulfment of all or only part of the mitochondria (Lemasters, 2014). Therefore, general autophagy and mitophagy are tightly connected, but may have distinct functional significance and multiple regulatory mechanisms in the heart. It is important to elucidate the interactions of the multiple distinct mechanisms in regulating mitophagy and autophagy. Though the beneficial effects of autophagy are mediated possibly, in part, through the elimination of damaged mitochondria, there are examples where autophagy and mitophagy may oppose each other. For instance, in a mouse model of Type 1 Diabetes, diminished autophagy can protect against diabetic heart injury, presumably through upregulated mitophagy and alternative autophagy (Xu et al., 2013). In ischemia/reperfusion injury, the loss of PINK1 increases the infarct size (Siddall et al., 2013). In cardiac-specific DRP1+/− mice, where mitophagy is inhibited, damage due to myocardial ischemia/reperfusion injury is exacerbated (Ikeda et al., 2015), suggesting a protective role of mitophagy during ischemia/reperfusion. However, haploinsufficiency of Beclin 1 that suppresses autophagy has been found to mitigate ischemia/reperfusion injury (Matsui et al., 2007), suggesting an opposite role of autophagy. The opposite effects of mitophagy and autophagy on ischemia/reperfusion remains to be determined. Further investigations are needed to distinguish mitophagy from general autophagy, and to better understand their distinct functional significance in the heart. Moreover, alterations in mitochondrial function have been increasingly recognized as a hallmark of several cardiovascular pathologies (Murphy et al., 2016; Saito and Sadoshima, 2015). If mitophagy emerges as a promising therapeutic target, pharmacological strategies to specifically modulate mitophagy are needed to determine the precise role of mitophagy in an array of cardiovascular stressors.

To summarize, current knowledge regarding mitophagy in the heart is limited. The magnitude and kinetics of mitophagy in various disease conditions is currently unknown. It remains to be elucidated how mitophagy connects to other cellular processes, such as general autophagy, mitochondrial fission/fusion, and mitochondrial biogenesis. Recent studies suggest mitophagy is a dynamic process that can be transiently activated and then downregulated in the heart in response to cardiac stress (Shirakabe et al., 2016). In addition, under some conditions, uncontrolled or excessive mitophagy may be detrimental (Liu et al., 2013; Saito and Sadoshima, 2015). To this end, it shall be critical to determine when and to what extent manipulating mitophagy activity may serve as a cardioprotective strategy. Moreover, it is essential to elucidate whether mitophagy activation is a viable therapeutical approach once cardiac mitochondrial damage has occurred, and to which specific pathological settings this is relevant. This field’s advancement hinges on the development of techniques that provide robust measurement of in vivo mitophagy, as well as novel methods to evaluate autophagy/mitophagy in human subjects.

Highlights.

  • Mitophagy is a specialized autophagic pathway that mediates the lysosomal clearance of damaged mitochondria.

  • Mitophagy plays a critical role in cardiovascular health.

  • Multiple distinct mechanisms regulate mitophagy.

  • Pharmacological approaches targeting mitophagy may have significant therapeutic benefits for cardiovascular disease

Acknowledgments

We apologize to the authors of several high-quality articles that we were not able to discuss and cite owing to space limitations.

Funding

This work was supported by grant from the National Institutes for Health to N.S. (K22-HL135051).

Footnotes

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Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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