Targeting mitochondrial quality control: Ginsenoside Rg1 as a therapeutic candidate for neuromuscular diseases

Abstract

Neuromuscular diseases (NMDs) are complex disorders caused by the dysfunction of motor neurons and skeletal muscles. They lead to progressive muscle weakness and atrophy and impose a significant economic burden on patients and society at large. The dysregulation of mitochondrial quality control (MQC), a key cellular process, contributes to the pathogenesis of several NMDs. Interestingly, accumulating evidence demonstrates that ginsenoside Rg1 can regulate MQC by modulating mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and mitocytosis, thus aiding with the management of several diseases. This review comprehensively summarizes the current understanding of ginsenoside Rg1's effects on mitochondrial function. Furthermore, it proposes that Rg1 may target MQC mechanisms, emerging as an effective active agent for the treatment of NMDs. This review aims to bridge existing knowledge gaps and establish a theoretical foundation for the clinical application of ginsenoside Rg1 in the treatment of NMDs characterized by MQC dysfunction.

Graphical abstract

1. Introduction

Mitochondria are highly dynamic cell organelles that play a key role in physiological processes such as energy production, energy metabolism, apoptosis, and intracellular calcium homeostasis. To maintain both the structural and functional integrity of mitochondria, mitochondrial quality control (MQC) is vital. MQC mechanisms not only eliminate damaged mitochondria but also replenish their components (e.g., proteins and lipids) through biogenesis, thereby ensuring cellular homeostasis [1]. These MQC processes include mitochondrial dynamics, biogenesis, mitophagy, and mitocytosis, all of which are vital for maintaining cell health. The dysregulation of MQC has been linked to a variety of diseases, including neurodegenerative disorders, cardiovascular diseases, and pulmonary diseases, among others [2]. As a result, research regarding therapeutic interventions targeting MQC mechanisms is warranted.

Neuromuscular diseases (NMDs) are caused by the dysfunction of motor neurons and skeletal muscles, leading to progressive muscle weakness and atrophy. Mitochondrial function influences the etiology of NMDs both directly and indirectly. Research has highlighted the prominent roles of mitochondria at both pre- and post-synaptic sites, suggesting their involvement in neuromuscular transmission defects [3]. The dysregulation of mitochondrial metabolism has also been implicated in NMDs, with alterations in processes such as the TCA cycle (involving ACO2 and MDH2), OXPHOS, and β-oxidation (involving CPTII, LCDA, and ECHS1) contributing to energy supply deficiencies that impair muscle and motor neuron function [4]. Importantly, alterations in MQC mechanisms are recognized as a hallmark of NMDs [5].

Panax ginseng Meyer, renowned for its extensive pharmacological effects, is known for nourishing the body and boosting immunity. It is particularly valued for its ability to support overall vitality and enhance immune function. Clinical studies have demonstrated the effectiveness of P. ginseng in combating diabetes, improving cardiovascular health, alleviating stress, and ameliorating cognitive dysfunction [6]. The primary active components of P. ginseng include ginsenosides, volatile oils, polysaccharides, alkaloids, and polyphenols, all of which contribute to its pharmacological properties. Among these, ginsenoside Rg1 is a key bioactive compound [7] and was first isolated and identified from P. ginseng by the Japanese natural chemist Shibata S [8]. As research into P. ginseng components has advanced, ginsenoside Rg1 has garnered immense attention within the scientific community. Several modern analytical techniques, such as HPLC and MS, have been employed to isolate and identify Rg1. These methods allow researchers to confirm the purity and structure of Rg1, laying the groundwork for further research. Ginsenoside Rg1 belongs to the class of tetracyclic triterpene saponins, with a molecular formula of C₄₂H₇₂O₁₄. Its unique molecular structure gives Rg1 distinctive biological activities and allows it to influence various physiological and pathological processes. Studies have shown that Rg1 offers cell protection and regulates physiological functions through multiple mechanisms, offering antioxidant [9], anti-inflammatory [10], and neuroprotective effects [11].

Despite its importance, our understanding of how ginsenoside Rg1 targets MQC to alleviate NMDs remains limited. This review aims to deepen our understanding of how ginsenoside Rg1 impacts MQC and proposes that it may serve as a therapeutic candidate for NMDs.

2. Ginsenoside Rg1 effectively regulates mitochondrial quality control mechanisms

Research has shown that ginsenoside Rg1 holds significant promise as a selective glucocorticoid agent and is capable of modulating immune responses without causing adverse effects [12]. According to the existing literature, ginsenoside Rg1 can inhibit the mitochondrial apoptotic pathway and ameliorate mitochondrial dysfunction through various signaling pathways, thus providing a protective effect (Table 1). For instance, the Nrf2/HO-1 pathway serves as a primary mechanism of intracellular defense against oxidative stress. In oxidative stress models, ginsenoside Rg1 can inhibit the mitochondrial apoptotic pathway by activating the Nrf2/HO-1 axis [13] and simultaneously modulating other oxidative stress-related factors. For instance, it can reduce the production of reactive oxygen species (ROS) and malondialdehyde (MDA) while enhancing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) [13,14,16]. ROS overproduction typically occurs due to the disruption of the mitochondrial respiratory chain. However, engineered mitochondrial ROS scavenger nanocomplexes can not only mitigate oxidative stress but also enhance drug biodistribution in the lungs and reduce inflammation, thereby ameliorating the symptoms of acute respiratory distress syndrome [17]. Interestingly, estrogen receptor alpha (ERα) is known to exert protective effects in ischemia-reperfusion (IR) injury models. Ginsenoside Rg1 activates ERα, upregulates YAP expression, and alleviates IR-mediated liver injury [16].

Table 1.

Inhibitory effects of Rg1 on the mitochondrial apoptosis pathway under different types of stress.

Type of Stress	Model	Targets	References
Oxidative Stress	PM2.5 (400 l g/mL) induced-HUVECs	Nrf2/HO-1, ROS, MDA	[13]
	D-galactose-treated neural stem cells and mice	Akt/mTOR, SOD, GSH-px, ROS, MDA, p53, p16, p21, Rb	[14]
	Doxorubicin-induced mouse models of cardiac toxicity	Akt, Erk, Bcl-2/Bax, Cyt c, caspase-3, FS%, EF%, LDH, CKMB	[15]
	Ischemia–reperfusion injury-induced mouse models of liver fibrosis	Erα, YAP, ATP, ROS, MMP	[16]
Hypoxia	LPS‐ or H/R‐treated H9c2 cell, CLP-induced mouse model of sepsis	Akt/GSK-3β, ROS, MMP, respiratory chain complex I–IV, Mfn1, Mfn2, OPA1, Drp1, Fis1, Cyt c, Bcl-2/Bax, caspase-3, caspase-9, mitochondrial calcium, LDH	[18]
Inflammation	Chronic ethanol binge-induced mouse model of liver injury	ATP, ALT, ADH, CYP2E1, GSH-px, MDA, ROS, NLRP3, ASC, caspase-1, IL-1β, IL-18	[19]
	CRS-induced rat model, LPS-induced inflammatory stress model, and corticosterone-induced oxidative stress model in HAPI and PC-12 cells	GAS5/EZH2/SOCS3/NRF2, COX-2, iNOS, ROS, IL-1β, TNF-α, IL-6, ATP, MMP	[21]
Other Types of Stress	Mce-induced cellular model of NAFLD	SPHK1, SGPL1, Bcl-2/Bax, AKT, Erk1/2	[22]
	Glucocorticoid-induced model of learning and memory impairments and neuronal apoptosis in 12-month-old male mice	caspase-3, caspase-9, Cyt c, ALT, AST, CypD, MMP, CRC	[23]

ADH: alcohol dehydrogenase; Akt: protein kinase B; ALT: alanine transaminase; ASC: apoptosis-associated speck like CARD-domain containing protein; AST: aspartate aminotransferase; ATP: adenosine triphosphate; Bcl-2: B-cell lymphoma-2; Bax: BCL2-Associated X Protein; CKMB: creatine kinase MB; COX-2: cyclooxygenase-2; CRC: mitochondrial calcium retention capacity; CRS: chronic restraint stress; Cyt c: cytochrome c; CypD: cyclophilin D; CYP2E1: Cytochrome P4502E1; Drp1: dynamin-related protein 1; EF%: ejection fraction%; Erk1/2: extracellular regulated protein kinases 1/2; Erα: estrogen receptor alpha; EZH2: Enhancer of zeste homolog 2; Fis1: mitochondrial fission 1 protein; FS%: fractional shortening%; GAS5: growth arresting-specific 5; GSH: glutathione; GSH-px: glutathione peroxidase; GSK-3β: glycogen synthase kinase-3β; HUVECs: human umbilical vein endothelial cells; H/R: hypoxia/reoxygenation; IL: Interleukin; iNOS: inducible nitric oxide synthase; LDH: lactate dehydrogenase; MDA: malondialdehyde; mTOR: mammalian target of rapamycin; MMP: mitochondrial membrane potential; Mfn1/2: mitofusin-1/2; NAFLD: nonalcoholic fatty liver disease; NLRP3: The NOD-, LRR-, and pyrin domain-containing protein 3; NO: nitric oxide; NOS: nitric oxide synthase; NRF2: nuclear respiratory factor 2; OPA1: optic atrophy protein-1; ROS: reactive oxygen species; SPHK1: sphingosine kinase 1; SGPL1: Sphingosine-1-phosphate lyase 1; SOD: superoxide dismutase; TNF-α: tumor necrosis factor-α; YAP: Yes-associated protein.

Furthermore, in models of inflammatory stress, NLRP3 inflammasome activation occurs, leading to the increased production of inflammatory cytokines. Notably, ginsenoside Rg1 can inhibit NLRP3 activity, produce anti-inflammatory effects, and suppress the mitochondrial apoptotic pathway, thereby playing a hepatoprotective role in murine models of alcoholic liver disease [19]. Additionally, certain herbal medicines, such as Argemone mexicana root extracts, also confer protective effects through their anti-inflammatory properties [20].

In conclusion, ginsenoside Rg1 can suppress the mitochondrial apoptotic pathway and confer protection against multiple pathological conditions. When MQC mechanisms are imbalanced, the mitochondrial apoptotic pathway is often triggered, leading to apoptosis. Given that ginsenoside Rg1 closely affects the mitochondrial apoptotic pathway, a key question arises: can ginsenoside Rg1 modulate MQC mechanisms? Based on the existing evidence, it appears that ginsenoside Rg1 could be an effective agent for targeting MQC mechanisms and improving disease outcomes.

2.1. Ginsenoside Rg1 regulates mitochondrial dynamics

A key aspect of MQC is the substantial adaptability of mitochondrial dynamics. This flexibility allows mitochondria to constantly alter their structure through the processes of fusion and fission. Mitochondrial dynamics are crucial for repairing damaged mitochondrial components because they facilitate material exchange between healthy and damaged mitochondria during fusion and enable the elimination of defective parts during fission. The fusion process occurs in two stages; the fusion of the outer mitochondrial membrane occurs first and is followed by the merging of the inner membrane. This sequence is regulated by several proteins, including Mitofusin-1 (Mfn1), Mitofusin-2 (Mfn2), and Optic Atrophy 1 (Opa1). Conversely, mitochondrial fission, which divides a single mitochondrion into two separate units, is controlled by Mitochondrial Fission 1 protein (Fis1), Dynamin-Related Protein 1 (Drp1), and Mitochondrial Fission Factor (MFF) [24].

Research shows that in animal models, ginsenosides can significantly attenuate abnormalities in the expression of mitochondrial Drp1 and Mfn2 under pathological states. These compounds can also promote the repair of mitochondrial membranes, improve the structure of mitochondrial cristae, and prevent chromatin condensation, thereby enhancing overall mitochondrial function [25,26]. Notably, the therapeutic potential of ginsenosides extends beyond general mitochondrial modulation, with specific subtypes of these compounds offering distinct advantages. Specifically, in cases of Aβ_25-35-induced cell damage, Rg1 outperforms Rb1, Rd, and Re in enhancing mitochondrial content, increasing mitochondrial interconnectivity, and reducing mitochondrial circularity [27]. These benefits warrant further exploration of the molecular mechanisms underlying the effects of Rg1, particularly its interactions with key regulatory proteins. Recent in vitro and in vivo studies have revealed that ginsenoside Rg1 interacts with Glutathione S-transferase pi (GSTP1), blocking the S-glutathionylation of OPA1 by GSTP1. This promotes the interaction of OPA1 with mitochondrial filaments, helping to maintain the structure of mitochondrial cristae, preserve mitochondrial integrity, and improve heart muscle function [28]. A study led by Kefei Chu demonstrated that ginsenoside Rg1 increases the phosphorylation of Drp1 at Ser 637 in an AMPK-dependent manner, inhibiting mitochondrial division and reducing pyroptosis in human periodontal ligament cells exposed to bacterial lipopolysaccharide (LPS) [29]. The growing understanding of Rg1's effects on regulatory pathways highlights its potential as a versatile therapeutic agent.

The balance between fusion and fission is crucial for maintaining mitochondrial health, as it governs the dynamics of mitochondrial networks. Disruptions in these processes can lead to mitochondrial dysfunction, contributing to a range of disorders, such as cognitive impairment [25]. Understanding how ginsenoside Rg1 modulates these dynamics could enable the development of therapeutic strategies aimed at enhancing mitochondrial function and resilience in various pathological conditions.

2.2. Ginsenoside Rg1 regulates mitophagy

Mitophagy is a crucial MQC mechanism in which aged and damaged mitochondria are selectively eliminated through targeted sequestration and engulfment, followed by lysosomal degradation. This process is primarily regulated by the PINK1-Parkin pathway [30]. Ginsenoside Rg1 has been shown to regulate the PINK1/Parkin signaling pathway, either directly or indirectly, to facilitate mitophagy. As a result, it can help in maintaining mitochondrial quality and preserving mitochondrial function.

In various disease models, Rg1 directly inhibits the activation of the PINK1/Parkin pathway, thereby suppressing mitophagy. This suppression manifests as a significant reduction in the ratio of the LC3-II/LC3-I proteins and an increase in the expression levels of the SQSTM1/p62 proteins [31,32], all of which are involved in autophagy. Importantly, these effects cannot simply be attributed to the regulation of basal autophagy. While LC3-II/LC3-I and SQSTM1/p62 are canonical autophagy proteins, their dynamic changes in this context specifically indicate the modulation of mitophagy by Rg1, rather than general autophagy alterations. Additionally, both in vitro and in vivo studies indicate that Rg1 can indirectly facilitate mitophagy via the SIRT1/PINK1/Parkin and aldolase/AMPK/PINK1 signaling pathways [33,34]. This suggests that Rg1 can regulate mitochondrial autophagy through both direct and indirect mechanisms; however, the specific regulatory mechanisms still require further exploration. Nevertheless, current evidence also indicates that post-translational modifications of proteins play a critical mediatory role in the regulation of mitochondrial autophagy by Rg1. For instance, Ni Wang et al. [35] found that in Alzheimer's disease models (i.e., transgenic mice with cognitive defects and AβO-treated cells), Rg1 inhibits the phosphorylation of mTOR at Ser 2448, ULK1 at Ser 757, and AMPK at T172. Furthermore, it decreases p62 expression while increasing OPTN and LC3B expression, thereby initiating mitophagy. In this study, post-treatment observations using electron microscopy also revealed an increase in mitophagosomes, suggesting that Rg1 effectively restores mitophagy, helping to prevent apoptosis.

2.3. Ginsenoside Rg1 regulates mitochondrial biogenesis

Mitochondrial biogenesis is the process responsible for generating new, functional mitochondria to replace damaged ones and plays a critical role in maintaining MQC. The key markers of mitochondrial biogenesis include the copy number of mitochondrial DNA (mtDNA), an elevated mtDNA:nDNA ratio, and the expression levels of mitochondrial genes [36]. Key transcription factors that regulate this process include peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), nuclear respiratory factor 1 (Nrf1), and mitochondrial transcription factor A (TFAM). Upon activation, PGC-1α translocates to the nucleus, where it stimulates Nrf1. Nrf1 subsequently triggers the transcription of nuclear-encoded respiratory chain components and TFAM. This cascade promotes mitochondrial protein synthesis, mtDNA replication and transcription, and the de novo biosynthesis of mitochondria [37].

Rg1 treatment has been shown to significantly enhance the expression of key transcription factors involved in mitochondrial biogenesis — including PGC-1α, Nrf2, Nrf1, TFAM-1, and components of respiratory chain complexes III and IV — across various disease models [31,38]. Mechanistic studies have demonstrated that in cellular and rat acute lung injury (ALI) models, Rg1 reduces the expression of F-Box Protein 3 (FBXO3) in an N6-methyladenosine (m6A)-YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-dependent manner. FBXO3, a component of the ubiquitin-proteasome system, plays a role in the degradation of PGC-1α, thereby regulating mitochondrial biogenesis. By inhibiting FBXO3, Rg1 stabilizes PGC-1α, increasing its availability in the nucleus and enhancing its transcriptional activity. This reduction activates the PGC-1α/Nrf2 pathway, which in turn regulates key mitochondrial biogenesis genes, such as cytochrome C (CYCS) and NADH dehydrogenase ubiquinone oxidoreductase subunit C2 (NDUFC2), thus promoting mitochondrial biogenesis and alleviating sepsis-induced ALI [39]. Furthermore, Rg1 treatment has been shown to increase the protein expression of Sirtuin 1 (Sirt1) in cardiomyocytes [40]. Sirt1 deacetylates PGC-1α, which influences mitochondrial biogenesis. This process enhances the stability of PGC-1α and promotes its transcriptional activity on mitochondrial genes, ultimately bolstering MQC processes. Additionally, Sirt1 activation by Rg1 also appears to improve mitochondrial function via the deacetylation of other critical mitochondrial proteins, thereby enhancing their activity [36].

The significance of mitochondrial biogenesis cannot be overstated, as this process directly impacts cellular energy production, metabolism, and overall cellular health. The ability of Rg1 to enhance this process underscores its therapeutic potential in conditions characterized by mitochondrial dysfunction. Moreover, as mitochondrial biogenesis is linked to metabolic regulation, such as in type 2 diabetes mellitus [41], Rg1 may also play a role in the management of metabolic disorders [42].

2.4. Ginsenoside Rg1 regulates mitocytosis

Mitocytosis is a recently discovered MQC mechanism and was first identified in 2021 by Yu Li's team at Tsinghua University. This mechanism involves migrasomes that eliminate damaged mitochondria during cell migration. Specifically, under mild mitochondrial stress, damaged mitochondria are selectively transported into migrasomes, which are then expelled from migrating cells. This process is critical for maintaining mitochondrial membrane potential (MMP) and overall cell viability [43].

Evidence indicates that ginsenoside Rg1 may improve mitocytosis by alleviating functional impairments in migrating cells. Rg1 plays a significant role in inflammatory responses by promoting neutrophil migration and suppressing inflammation [44]. For instance, Rg1 can increase the number of neutrophils in the peritoneal cavity of septic mice, suppress inflammatory responses, and significantly improve the survival rates of these mice [45]. Additionally, Rg1 reduces lung inflammation by regulating the infiltration of neutrophils and M2 macrophages in mice [46]. Furthermore, Rg1 enhances the migration and function of endothelial progenitor cells [47] and olfactory ensheathing cells [48], improving overall cellular functionality.

As mentioned earlier, Rg1 also affects MQC by modulating the phosphorylation of Drp1, a key protein involved in mitochondrial fission that aids in clearing damaged mitochondria during mitocytosis [49]. Given that Drp1 is essential for mitocytosis and that cell migration is a prerequisite for this process, Rg1 may potentially promote mitocytosis by regulating Drp1, thereby enhancing MQC efficiency. This, in turn, helps in maintaining mitochondrial homeostasis and cellular function, providing a novel therapeutic approach for treating diseases characterized by MQC impairments.

In summary, ginsenoside Rg1 can regulate MQC through its effects on mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and mitocytosis (Table 2, Fig. 1).

Table 2.

Mechanisms through which Rg1 regulates mitochondrial quality control (MQC).

MQC Process	In vitro/in vivo	Model	Target	References
Mitochondrial Dynamics	In vivo (i.g.)	Hindlimb suspension (HLS)-induced rat model of cognitive deficits	Drp1, Mfn2, BDNF-TrkB/PI3K-Akt, Tomm20, complex I, Bax/Bcl-2, caspase-3, Cyt c, SOD, MDA, GSH-Px, H2O2	[25]
	In vivo (i.g.)	Chronic sleep deprivation stress (CSDS)-induced mouse model of cognitive deficits	Drp1, Mfn2, Nrf2, AMPK-Sirt3, Bax/Bcl-2, caspase-3, caspase-9, SOD, CAT, MDA, HO-1, ATP	[26]
	In vitro	Aβ25-35-induced cell damage	mitochondrial content, interconnectivity, minor axis and circularity, OCR, MMP, ROS, ATP	[27]
	In vivo (i.p.), in vitro	LPS-induced mouse model of cardiac injury and primary neonatal rat ventricular myocytes (NRVMs)	GSTP1/OPA1, ATP, mtDNA copy number, ROS, GSH/GSSG	[28]
	In vitro	LPS-induced pyroptosis in human periodontal ligament cells (HPDLCs)	Drp1, NLRP3, ASC, caspase-1, GSDMD-NT, ROS, MMP, ATP, LDH, IL-1β, IL-18	[29]
Mitophagy	In vitro	OGD-induced cellular apoptosis	LC3B II, p62, Beclin-1, ROS, MTP	[31]
	In vivo (i.v.), in vitro	I/R-induced liver injury in rats and OGD/R-induced injury in cells	LC3-II/LC3-I, PINK1/Parkin, SQSTM1/p62, MMP, ALT, AST	[32]
	In vivo (i.g.), in vitro	Ligating the left anterior descending coronary artery (LAD)-induced mouse model of myocardial infarction and H2O2-induced cardiac injury in cells	SIRT1/PINK1/Parkin, LC3-I, LC3-II, p62, fibrotic makers α-SMA and collagen III	[33]
	In vivo (i.g.), in vitro	Starvation-induced mouse model of nutritional stress and glucose deprivation-induced nutritional stress in cells	aldolase/AMPK/PINK1, caspase-3, ADP/ATP, Mfn2, MMP	[34]
	In vivo (i.p.), in vitro	Transgenic mouse model with cognitive defects, AβO-treated cells	PINK1/Parkin, mTOR, ULK1, AMPK, p62, OPTN, LC3B, LAMP1 (lysosome marker), TOM20 (OMM marker), Bcl2L13, BINP3L, Fundc1, caspase-9	[35]
Mitochondrial Biogenesis	In vitro	OGD-induced cellular apoptosis	PGC-1α, NRF-1, TFAM-1, ROS, MTP	[31]
	In vivo (i.p.)	Streptozotocin-induced rat model of diabetes	PGC-1α, complex III, complex IV, ROS, MAP, LDH, CKMB, AST, SOD, GSH, GPx, AMPK/Nrf2/HO-1, IL-1β, IL-6, TNFα, NF-κb, TLR4, NLRP3, ASC	[38]
	In vivo (i.v.), in vitro	Sepsis-induced ALI model in rats and LPS-induced ALI model in cells	PGC-1α/Nrf2, Bcl-2, Bax, caspase-3, ROS, MMP, IL-1β, IL-6, TNFα, FBXO3, CYCS, NDUFC2	[39]
	In vitro	Untreated cardiomyocytes and neurons	Sirt1, OCR, HKII	[40]
	In vitro	Aβ25-35-induced cell damage	Basal respiration, ATP, spare capacity, maximal respiration	[27]

AMPK: AMP-activated protein kinase; AβO: β-amyloid oligomer; BDNF: brain-derived neurotrophic factor; Bcl2L13: BCL2 Like 13; BINP3L: BCL2 Interacting Protein 3 Like; CAT: catalase; CSDS: chronic sleep deprivation stress; CYCS: cytochrome C; FBXO3: F-Box protein 3; Fundc1: FUN14 domain-containing protein 1; GDH: glutamate dehydrogenase; GSTP1: Glutathione S-transferase pi; GSH/GSSG: glutathione/oxidized glutathione; GSDMD-NT: the pyroptotic effector protein GSDMD, performing an N-terminal domain; HLS: hindlimb suspension; HO-1: heme oxygenase-1; HPDLCs: human periodontal ligament cells; HKII: Hexokinase II; I/R: ischemia/reperfusion; LC3: microtubule-associated protein 1 A/1 B-light chain 3; LPS: lipopolysaccharide; LAMP1: lysosomal associated membrane protein 1; OCR: oxygen consumption rate; OGD/R: oxygen glucose deprivation/re-oxygenation; OPA1: optic atrophy protein-1; PCG-1α: peroxisome proliferator-activated receptor gamma coactivator-1α; PINK1: PTEN-induced putative kinase 1; PI3K: phosphoinositide 3-kinase; Sirt3: Sirtuin 3; SQSTM1: sequestosome-1; TrkB: tropomyosin receptor kinase B; TLR4: Toll-like receptor 4; Tomm20: translocase of outer mitochondrial membrane 20; ULK1: UNC51-like kinase-1; MAP: mean arterial pressure; MTP: mitochondrial transmembrane potential; NF-κB: nuclear factor kappa-B; NRF1: nuclear respiratory factor 1; NRVMs: neonatal rat ventricular myocytes; NDUFC2: NADH dehydrogenase ubiquinone oxidoreductase subunit C2.

Fig. 1.

Ginsenoside Rg1 regulates mitochondrial quality control. Mitochondrial dynamics: This process includes the fission of a single mitochondrion into two mitochondria, mediated by the mitochondrial proteins Fis1, MFF, Drp1, MiD 49, and MiD 50, and the fusion of two mitochondria into a single mitochondrion, mediated by the mitochondrial proteins OPA1 and Mfn1/2. Mitophagy: After mitochondrial damage, the PINK1/Parkin signaling pathway is activated, and damaged mitochondria are encapsulated by autophagosomes to generate mitochondrial autophagosomes, which are subsequently phagocytosed and degraded by lysosomes. Mitochondrial biogenesis: PGC-1α enters the nucleus, where it stimulates Nrf1/2. Nrf1/2 then triggers the transcription of nuclear-encoded components of the respiratory chain and TFAM, promoting mitochondrial protein synthesis, mtDNA replication and transcription, and mitochondrial gene expression. Mitocytosis: Migrating cells form migrasomes, and damaged mitochondria are transported to migrasomes for elimination via the assistance of Drp1, HIF5B, and Myo 19. Created using Figdraw 2.0: www.figdraw.com.

3. Mitochondrial quality control dysfunction is a key pathologic mechanism in neuromuscular diseases

NMDs are a heterogeneous group of genetic and clinical disorders characterized by damage to or dysfunction of the neuromuscular system, including peripheral motor neurons, skeletal muscles, and neuromuscular junctions [4]. Complications associated with NMDs not only increase the severity of existing comorbidities but also create therapeutic challenges and increase healthcare costs, leading to a significant economic burden (Fig. 2). Therefore, it is essential to develop more effective treatment strategies for both NMDs and their complications while also identifying potential therapeutic targets.

Fig. 2.

Overview of neuromuscular diseases (NMDs) and key pathologic mechanisms. NMDs are associated with high rates of complications and substantial economic burden. The imbalance of mitochondrial quality control is a key pathologic mechanism of NMDs.

Research indicates that MQC plays an important role in NMDs (Table 3, Table 4, Table 5). To present a clear, logical, and relatively comprehensive overview of the role of MQC, this review will focus on three major NMDs: myasthenia gravis (MG), which has been relatively underexplored; Duchenne muscular dystrophy (DMD), which has been studied more frequently; and amyotrophic lateral sclerosis (ALS), which is widely researched. Ultimately, the evidence collectively shows that MQC mechanisms are closely linked to the pathogenesis of NMDs.

Table 3.

Mitochondrial quality control in the context of MG.

MQC Process	Model	Targets	References
Mitochondrial Dynamics	R97–116 peptides-induced rat model of EAMG	Mfn1, Mfn2, Drp1, OPA1, Fis1, mitochondrial respiratory chain complex	[51]
	MG patient	Drp1, Tom20, Opa1, Mfn1, Mfn2, OMA1, PDH, Pex14, VDAC, MFF, OCR	[52]
Mitophagy	H2O2- and carbonyl cyanide m-chlorophenylhydrazone (CCCP) -treated L6 myoblasts	PINK1/Parkin, MDA, ROS, SOD, ATP, Tom20, Tim23, VDAC1, LC3 II, P62	[53]
	R97–116 peptides-induced rat model of EAMG	pink 1, Parkin, LC3II, Bcl-2, p62, Cyt c, Bax, caspase-3, caspase-9	[54]
Mitochondrial Biogenesis	R97–116 peptides-induced rat model of EAMG	AMPK/PGC-1α, Nrf1, Tfam, COX lV, SOD, GSH-px, MDA, Na+/K + -ATPase, Ca2+/Mg2+-ATPase	[55]

CCCP: carbonyl cyanide m-chlorophenylhydrazone; EAMG: experimental autoimmune myasthenia gravis; Pex14: peroxisomal biogenesis Factor 14; Tim23: mitochondrial import inner membrane translocase subunit Tim23; VDAC: voltage-dependent anion channel; VDAC1: recombinant voltage dependent anion channel protein 1.

Table 4.

Mitochondrial quality control in the context of DMD.

MQC Process	Model	Targets	References
Mitochondrial Dynamics	mdx mice	Drp1, Mfn2, PGC-1α, mtDNA, activity of creatine kinase, AST, LDH, Ca2+, CypD, ANT1, ANT2, ATP, complex I-IV, TBARS	[57]
	mdx mice	Dnm1l, Opa1, Mfn1, Arntl, Cry1/2, Per2, Nr1d1, Esrra, Sirt1, Map1lc3b, Sqstm1, BNIP3, PPARGC1A	[58]
	mdx mice	Mfn1, Mfn2, Fis1, PINK1/parkin, LC3-I, LC3-II, SQSTM1, UKLK1	[60]
Mitophagy	mdx mice	Map1lc3b, SQSTM1, BNIP3, Becn1	[58]
	mdx mice	PINK1, Bnip3, Becn1, Map1lc3b, Sqstm1, Atg5, Atg 7, Lamp1	[59]
	mdx mice	PINK1/parkin, LC3-I, LC3-II, SQSTM1, UKLK1, Mfn1, Mfn2, Fis1	[60]
	mdx mice	PINK1, Parkin, Bnip3, Fundc1, Bcl2L13, Becn1, Atg5, Map1lc3b, p62, Tfeb, Lamp1, LC3-II/L3-I, 4EBP1	[61]
	mdx mice	Parkin, LC3 (II/I), SQSTM1/p62, MHC, MyoD, myogenin	[62]
Mitochondrial Biogenesis	mdx mice	PGC-1α, Esrra	[58]
	mdx mouse	PGC-1α, Kyat1, Kyat 3, Got2, TNF, IL 6, II1β, KMO, KYN, 3-HK	[63]
	D2-mdx mice	PGC-1α, IL-6, TLR4, BAX/Bcl2, caspase-3, oxidases A and B	[64]
	mdx mice	PGC-1α, dystrophin, MHC	[66]
	primary skeletal muscle cells from mdx mice	PGC-1α, Ca2+, TRPC-1, MyoD, H2O2, O2, 4-HNE, SOD2, CAT, GPx, TNF, SOD, GSR, myogenin, MHC-Slow, mTOR, PPARδ	[67]

Atg5/7: autophagy-related gene 5/7; ANT1/2: adenine nucleotide translocase 1/2; Arntl: aryl hydrocarbon receptor nuclear translocator-like 1; Becn1: beclin-1; Bnip3: Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3; Cry1/2: cryptochrome 1/2; Dnm1l: Dynamin 1 Like; Esrra: estrogen related receptor alpha; Got2: glutamic-oxaloacetic transaminase 2; GSR: glutathione-disulfide reductase; Kyat1/2: kynurenine aminotransferase 1/2; KYN: kynurenine; KMO: kynurenine monooxygenase; Per2: transcriptional repressors period 2; PPARδ: peroxisome proliferators-activated receptor-α; TBARS: thiobarbituric acid-reactive substances; Tfeb: transcription factor EB Gene; TRPC-1: transient receptor potential channel 1; UKLK1: UNC-51-like kinase 1; Map1lc3b: microtubule-associated proteins 1 light chain 3 beta; mdx: muscular dystrophy X-linked mouse; MHC: major histocompatibility complex; MyoD: myogenic differentiation; Nr1d1: nuclear receptor subfamily 1 group D member 1; 3-HK: 3-hydroxykynurenine; 4EBP1: eukaryotic initiation factor 4 E-binding protein 1; 4-HNE: 4-hydroxynonenal.

Table 5.

Mitochondrial quality control in the context of ALS.

MQC Process	Model	Targets	References
Mitochondrial Dynamics	Drosophila Sod1 knock-in model of ALS	Drp1, mitochondrial morphology, mitophagy	[69]
	SOD1G93A mice	OPA1, OCR, mitochondrial respiration, ATP, mitochondrial compartments,	[70]
	ALS patient-derived	Mfn2	[71]
	Mice carrying the wobbler point mutation in the VPS54 gene	Mfn1, Mfn2, Opa1, Drp1, pDrp1, OMA1, CaMKII	[72]
	Human tissue samples from ALS patients, tau-2N4R (tau) and Synaptoneurosome (SN)-treated cells	Drp1, pTau-S396, tau, caspase-3, Tomm20, and mitochondrial mass, density, and length	[73]
	SOD1G93A mice, 1.76 ng RNA (SOD1 G93A and TDP-43 Q331K)-induced zebrafish model of ALS, primary neuronal culture models, iPSC-derived human MNs	Drp1, p-Drp1S616, Fis1, mitochondrial length, caspase-3, PP1, complex I	[74]
	C9ORF72-knockout cells	FIS1, BAP31, C9ORF72, SMCR8	[75]
	CHCHD10 transgenic mouse variants (WT, R15L, & S59L), TDP-43 transgenic mice, FTLD-TDP patient brains	Opa1, Drp1, Mfn2, CHCHD10, ATP, OCR, basal respiration, maximal respiration, MICOS subunits (mitofilin, Mic 19, Mic 23)	[76]
	Patient fibroblasts, mouse models expressing the same CHCHD10 variant (p.Ser59Leu)	OPA1, SLP2, PHB1, PHB2, OMA1	[77]
	C9-ALS-associated proline–arginine dipeptide repeat proteins-treated NSC-34 mouse motor neurons	SIRT3/OPA1, caspase-3, ROS, Mfn2, Fis1, Drp1	[78]
Mitophagy	SOD1G93A mice	Fundc1, Bax, Bcl-2, LC3B-II (LC3I, LC3II), P62, TOM20, COXIV, HSP60, FOXD3	[79]
	PBMCs of sporadic (sALS) patients	PINK1, LC3-II/LC3-I, Beclin-1	[80]
	SOD1G93A mice	P62, PINK1, Parkin, Tom 40, LAMP1, LC3B, p-AMPKα, AMPKα, CTSD, NDUFA10, SDHB, UQCRFS1, ATP5a	[81]
	primary cultured neurons with mutations in UBQLN2	Parkin, Mfn2, UBQLN2, HSP60, HSP70, TOM20, COX IV	[82]
	Cells with mutations in TBK1	Parkin, TBK1, OPTN, LC3	[83]
	CHCHD10R15L and CHCHD10S59L mice	PARL/PINK1, Parkin, Tom20	[84]
	VapBP56S zebrafish	LC3, Tomm20, PGC-1α	[85]
	SOD1G93A mice	TBK1, VADC 1, LC3-II, OPTN, p62	[86]
	SOD1G93A mice	P62, LC3-I, LC3-II, BAX, Bak, Bcl-xl, Bcl-2, Cyt c, optineurin, VADC 1	[87]
	ALS patients	miR-335–5p, P62, ROS, SOD, β-actin, caspase-3, caspase-7	[88]
	SOD1G93A mice	NAD+, Iba 1, TNF-α, INF-γ, IL-1β, IL-2, IL-6, GCL, GGT, SOD1, SOD2, HMOX2, Sirt1, Sirt3, Nrf2, β-actin, ROS, mtATP, mtCa2+, caspase-3, PGC-1α, LC3-II, P62, PAR, complex I, VADC, Cyt c, H2O2, O2, SOD2, GSH, ATP, MMP	[89]
Mitochondrial Biogenesis	SOD1 transgenic mice (TgSOD1-G93 A/PGC-1α)	PGC-1α, complex I, complex IV, JNK, p38 MAPK	[90]
	SOD1G93A mice and ALS patients	PGC-1α, Nrf1, Nrf2, Tfam, mnSOD	[91]
	SOD1G93A mice	AMPK/SIRT1/PGC-1α, AMPK/SIRT1/IL-1β/NF-κB, ATP, MDA, Uqcrfs1, Cox5a, ATP5a, Ndufa10, SDHB	[92]
	SOD1G93A mice and SOD1G93A worms	AMPK/PGC-1α/Nrf1/Tfam, Uqcrfs1, ATP5a, Cyt c, SDHB, Cox5a, ATP, lipid peroxidation levels	[93]

ALS: amyotrophic lateral sclerosis; Atg 12: autophagy-related 12; BAP31: B cell receptor-associated protein 31; CaMKII: Ca2+/calmodulin kinase; CTSD: cathepsin D; CHCHD10: coiled-coil-helix-coiled-coil-helix domain containing 10; C9ORF72: chromosome 9 open reading frame 72; Cox5a: cytochrome c oxidase subunit 5 A; FOXD3: forkhead box D3; FTLD-TDP: frontotemporal lobar degeneration with TDP-43 pathology; GCL: γ-Glutamylcysteine ligase, catalytic subunit; GGT: γ-Glutamyl transpeptidase; HSP60: heat shock protein 60; HMOX2: heme oxygenase 2; Iba 1: ionized calcium-binding adapter molecule 1; INF-γ: Interferon γ; JNK: c-jun N-terminal kinase; LAMP1: lysosomal associated membrane protein 1; MICOS: mitochondria contact site and cristae organization system; NDUFV1: NADH: ubiquinone oxidoreductase core subunit V1; NDUFA10: NADH: ubiquinone oxidoreductase subunit A10; OMA1: OMA1 zinc metallopeptidase; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PHBs: prohibitins; PAR: protease activated receptor; PARL: presenilin-associated rhomboid-like protein; PBMCs: peripheral blood mononuclear cells; SDHA: succinate dehydrogenase complex flavoprotein subunit A; SDHB: succinate dehydrogenase complex iron sulfur subunit B; SLP2: Stomatin-Like Protein 2; SOD1: copper-zinc superoxide dismutase; STAT3: signal transducer and activator of transcription 3; SMCR8: Smith-Magenis chromosome region 8; TBK1: TANK-binding kinase 1; TDP-43: trans-active response DNA binding protein 43 kDa; UQCRFS1: ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1; UBQLN2: ubiquilin 2.

3.1. Pathologic mechanisms related to mitochondrial quality control in myasthenia gravis

MG is an autoimmune disorder caused by antibodies that attack acetylcholine receptors or similar molecules located on the postsynaptic membranes of neuromuscular junctions. Such attacks lead to skeletal muscle weakness, which is the primary clinical manifestation of MG. The muscle weakness can be widespread or localized, often affecting proximal muscles more than distal ones, and almost always involving the ocular muscles. This results in symptoms such as double vision (diplopia) and drooping eyelids (ptosis) [50].

In terms of mitochondrial dynamics, researchers have found novel heterozygous variants of the mitochondrial fission factor (MFF) gene in MG patients [52]. Furthermore, the aberrant expression of mitochondrial dynamics-related proteins has been observed in both MG patients and EAMG rats, a model of myasthenia gravis [51,52]. Interestingly, the aberrant expression of mitophagy-related proteins has also been noted in EAMG rats. The natural compound astragaloside IV (AS-IV) has been shown to regulate mitophagy and ameliorate MG-related muscle injury through the PINK1/Parkin signaling pathway [53,54]. With regard to mitochondrial biogenesis, Jiao W. et al. Discovered that the expression of PGC-1α and other related proteins is significantly downregulated in EAMG rats. A compound often used in traditional Chinese medicine was found to reverse these abnormalities by activating the AMPK/PGC-1α signaling pathway, thereby promoting mitochondrial biogenesis [55]. Collectively, these findings show that the dysregulation of MQC is closely associated with the pathogenesis of MG (Table 3).

3.2. Pathologic mechanisms related to mitochondrial quality control in duchenne muscular dystrophy

DMD is a severe, progressively debilitating NMD characterized by worsening motor dysfunction, the eventual need for respiratory support, and premature mortality. This condition is caused by pathogenic variants in the DMD gene, which encodes the protein dystrophin. In the absence of dystrophin, muscle fibers become highly vulnerable to injury, leading to a continuous decline in both muscle integrity and function, as well as the development of cardiomyopathy [56]. Studies indicate that DMD is closely associated with MQC (Table 4).

3.2.1. Mitochondrial dynamics

Dubinin M. V. et al. Showed that the expression of mitochondrial kinetic markers is significantly altered in DMD mouse models, i.e., mdx mice [57]. Moreover, this difference is not influenced by the light–dark cycle [58].

3.2.2. Mitophagy

Recent studies have identified abnormalities in the mRNA and protein levels of mitochondrial autophagy genes and autophagy regulators in the gastrocnemius muscle of DMD mice across various ages [58,59]. Kang C. and colleagues further demonstrated that these alterations are closely related to defects in the PINK1/Parkin signaling cascade [60]. Interestingly, Sebori R. et al. Showed that the natural compound resveratrol can counteract these defects and alleviate pathological changes in mdx mice [61], suggesting that natural compounds may provide therapeutic advantages. Additionally, recent studies have shown that treatments such as light-emitting diode therapy (LEDT) and idebenone (IDE) administration enhance the autophagic process in mdx mice, helping to alleviate muscle degeneration [62]. In conclusion, these insights suggest that ginsenoside Rg1, a natural compound, may target mitochondrial autophagy — particularly the PINK1/Parkin axis — emerging as a promising therapeutic agent for mdx mice.

3.2.3. Mitochondrial biogenesis

Several recent studies have demonstrated the aberrant expression of mitochondrial biogenesis genes, such as PGC-1α, in mdx mice [58,63,64]. Given these findings, it is imperative to speculate whether targeting mitochondrial biogenesis could be beneficial for the treatment of DMD. A review of the literature indicates that transgenic PGC-1α mice exhibit significant improvements in DMD-related parameters [65]. Furthermore, exercise interventions improve muscle morphology in mdx mice, increasing the expression of the mitochondrial biogenesis-related gene PGC-1α [66]. Additionally, Rocha G. L. D. et al. Reported that Tempol can also ameliorate injury in cellular models of DMD by increasing PGC-1α expression [67]. These studies suggest that the modulation of PGC-1α levels in skeletal muscle may represent a novel therapeutic strategy for the prevention or treatment of DMD.

3.3. Pathologic mechanisms related to mitochondrial quality control in amyotrophic lateral sclerosis

ALS is a progressive neurodegenerative disorder that leads to the loss of both upper and lower motor neurons, leading to impairments in voluntary muscle function and causing muscle atrophy [68]. Evidence from multiple studies links MQC impairment to ALS pathogenesis (Table 5).

3.3.1. Mitochondrial dynamics

In their study on ALS models, Nemtsova Y. et al. Detected abnormal mitochondrial morphology within neuronal cells. Interestingly, they found that downregulating the pro-fission factor Drp1 could reverse the decrease in mitochondrial networks at synaptic sites [69]. Meanwhile, Méndez-López I. et al. Demonstrated that even before the onset of clinical symptoms, the accumulation of mutant SOD1^G93A protein in mitochondria and the downregulation of OPA1 could cause ultrastructural mitochondrial alterations, leading to mitochondrial dysfunction in ALS [70]. Interestingly, Vinciguerra C. et al. Discovered a family with a novel clinical MFN2 gene mutation and identified the first ALS-frontotemporal dementia (ALS-FTD) case associated with this mutation [71]. Together, these studies suggest that mitochondrial dynamics-related proteins — including Drp1, OPA1, and Mfn2 — may serve as therapeutic targets for addressing mitochondrial dysfunction and the associated neuronal degeneration in ALS.

In motor neurons, ROS regulation and the Ox-CaMKII-dependent activation of Drp1 disrupt the fission–fusion balance, leading to mitochondrial fragmentation and a self-reinforcing decline in neuronal integrity [72]. The dysregulation of Drp1, combined with other protein interactions (e.g., the interaction of pTau-S396 with Drp1 and the PP1-Drp1 signaling cascade) contributes to mitochondrial dysfunction in ALS models [73,74]. In recent years, FIS1 has emerged as a novel genetic interactor of C9ORF72, the most prevalent genetic cause of ALS [75]. The mutual regulatory effects of OPA1-mitofilin complexes, CHCHD10, and TDP-43 play critical roles in maintaining mitochondrial integrity and function in ALS-FTD [76]. Additionally, the instability of the PHB complex induces mitochondrial dysfunction in ALS due to the disruption of OPA1/Mitofilin interactions [77]. These findings highlight the pivotal role of proteins related to mitochondrial dynamics and their interactions in the pathogenesis of ALS, suggesting that their modulation could be a viable therapeutic strategy for treating multiple pathological aspects of ALS.

Notably, the literature suggests that natural compounds may exert neuroprotective effects in ALS by regulating mitochondrial dynamics. For example, Pectolinarigenin was found to effectively modulate mitochondrial dynamics by upregulating and deacetylating OPA1 while enhancing Drp1 expression, thus protecting motor neurons [78].

3.3.2. Mitophagy

The SOD1^G93A mouse model is frequently used to study ALS pathophysiology. Studies have revealed the marked downregulation of FUNDC1 in the spinal cords of SOD1^G93A mice, subsequently demonstrating that FUNDC1 overexpression can substantially enhance locomotion and prolong survival in these animals [79]. In recent clinical studies, peripheral blood mononuclear cells (PBMCs) derived from patients with sporadic ALS (sALS) were examined, and alterations in mitochondrial morphology and the inefficient turnover of damaged mitochondria caused by disrupted mitophagy pathways were observed [80]. In SOD1^G93A mice exposed to copper, the expression of mitophagy-related proteins such as Parkin and PINK1 is significantly reduced. Moreover, treatment with urolithin A (UA) has been found to reactivate mitophagy and ameliorate gastrocnemius muscle atrophy and motor deficits in ALS mice [81]. These findings underscore the pivotal role of mitophagy in ALS progression. Genetic mutations, proteins, and miRNAs collectively contribute to the pathogenesis of ALS through mitophagy modulation. Studies indicate that UBQLN2 mutations [82], TBK1 mutations [83], CHCHD10 mutations (R15L and S59L) [84], and VapB P56S mutation [85] disrupt mitophagy in ALS. OPTN gene therapy [86] and IGF-1 treatment [87] robustly inhibit ALS pathogenesis by enhancing mitophagy. In addition, the downregulation of miR-335–5 P in ALS can disrupt neuronal mitophagy dysfunction [88]. These observations confirm that mitophagy dysfunction is a critical pathological hallmark of ALS.

Notably, the combined administration of the natural compounds pterostilbene (PT) and nicotinamide riboside (NR) has been found to promote mitophagy and enhance neuromotor performance in ALS models [89]. This study further highlights that targeting mitophagy using natural compounds represents a viable therapeutic strategy for ALS.

3.3.3. Mitochondrial biogenesis

In 2011, Zhao W. et al. Revealed that PGC-1α overexpression can markedly enhance motor performance and prolong survival in SOD1^G93A mice, positioning PGC-1α as a promising therapeutic target for ALS [90]. Subsequently, Thau N. et al. Reported the downregulation of both mRNA and protein levels of PGC-1α and its regulatory elements NRF-1, NRF-2, and Tfam in human ALS postmortem spinal cord and motor cortex and muscle biopsy specimens from ALS patients [91]. These findings demonstrate that both animal and clinical models of ALS show dysfunctions in mitochondrial biogenesis. Therefore, mitochondrial biogenesis could serve as a potential target for ALS treatment. A review of the literature shows that A-1, an arctigenin derivative that activates AMPK and SIRT1, exerts its effects through the AMPK/SIRT1/PGC-1α axis [92]. Similarly, R13 — a prodrug of 7,8-dihydroxyflavone that selectively activates the TrkB signaling pathway — enhances mitochondrial biogenesis by activating the AMPK/PGC-1α/Nrf1/Tfam pathway [93]. Both compounds promote mitochondrial biogenesis, alleviate gastrocnemius muscle atrophy and motor deficits, and delay ALS progression, ultimately conferring neuroprotection. Hence, they could serve as potential agents for the management of ALS.

4. Ginsenoside Rg1 may be a therapeutic candidate for NMD treatment

In clinical practice, NMDs are treated using a variety of approaches [94], including gene therapy, molecular therapies, pharmacological therapies, and therapies targeting downstream genes. However, each of these therapeutic strategies presents inherent shortcomings. Gene therapy can cause off-target genetic alterations, induce immune responses against viral delivery vectors, and is expensive [96]. In molecular therapies, there are some concerns regarding targeted delivery, immunological safety, long-term efficacy, and genomic integrity [95]. Additionally, pharmacological treatments carry metabolic, behavioral, and skeletal side effects [97]. Consequently, discovering natural therapeutic agents that are both cost-effective and cause minimal adverse effects is exceptionally important from a public health perspective.

Based on the literature, we speculate that ginsenoside Rg1 may be one of the most useful natural compounds for the treatment of NMDs. The reasons are as follows: (i) MQC imbalance is a key pathological mechanism of NMDs, and ginsenoside Rg1 can significantly modulate MQC mechanisms, attenuate mitochondrial dysfunction, and play a protective role. Since downstream gene therapy [95] is widely recognized for its value in the management of NMDs, ginsenoside Rg1 can be used to target the downstream gene–MQC mechanism imbalance involved in the pathogenesis of NMDs. (ii) Ginsenoside Rg1 exerts protective effects on skeletal muscles and can reduce myoatrophy [98]. In addition, ginsenoside Rg1 offers neuroprotective effects, and prevents neuronal damage [11]. Therefore, given that NMDs are caused by impaired motor neuron and muscle function, ginsenoside Rg1 could help in the treatment of NMDs. (iii) Finally, ginsenoside Rg1 has glucocorticoid-like characteristics, and as a natural compound, does not cause any toxic side effects [12]. Glucocorticoids are among the key hormones used in the treatment of neuromuscular diseases. Additionally, there is clear evidence regarding other natural compounds that are effective against NMDs [[53], [54], [55],61,78,89].

In conclusion, due to these reasons, we believe that ginsenoside Rg1 could target MQC mechanisms, emerging as an effective potential candidate molecule for the treatment of NMDs (Fig. 3).

Fig. 3.

Schematic diagram describing the potential of ginsenoside Rg1 in treating neuromuscular disorders (NMDs). Patients with NMDs experience motor nerve and skeletal muscle dysfunction. Due to its pharmacological effects, ginsenoside may serve as a key potential active ingredient for the management of NMDs. Created using Figdraw 2.0: www.figdraw.com.

5. Conclusion

NMDs are characterized by a complex pathology and poor prognosis. They not only severely affect patients’ quality of life but also impose a significant socioeconomic burden. Existing treatments have numerous limitations and side effects, underscoring the urgent need for alternative therapies with fewer adverse effects. Ginsenoside Rg1 presents significant potential for clinical application in the treatment of NMDs, particularly due to its effects on MQC processes, which are compromised in several disorders. This review delineates the potential of ginsenoside Rg1 as an effective active compound for the treatment of NMDs due to its regulatory effects on MQC mechanisms, thereby addressing existing gaps in the field.

So far, literature reviews have primarily focused on the regulatory effects of Rg1 across pathological conditions such as neurological disorders [11], and metabolic diseases [47]. All these conditions are caused by pathological mechanisms closely associated with mitochondrial dysfunction. However, there remains a notable scarcity of comprehensive reviews on the specific regulatory mechanisms by which Rg1 affects mitochondrial processes. In this context, the current review serves as the first comprehensive account of the role of ginsenoside Rg1 in the regulation of MQC mechanisms and provides the first comprehensive summary of the evidence linking ginsenoside Rg1 to mitochondrial function (Table 1, Table 2). Based on this evidence, this review proposes — for the first time — that ginsenoside Rg1 may have the ability to regulate mitocytosis, a recently discovered MQC modality. Additionally, this review provides the first comprehensive and detailed summary of MQC mechanisms such as mitochondrial dynamics, mitophagy, and mitochondrial biogenesis in NMDs. Although some reviews have explored pre-mitochondrial dysfunction in NMDs, most of them have focused on the TCA cycle, oxidative stress, and inflammation [4,5]. Furthermore, while some reviews have highlighted the interconnections between ALS and mitochondrial dysfunction, they have concentrated on mitochondrial turnover, mitochondrial dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions [100], or on the genetic aspects of mitochondrial dysfunction in ALS [101]. Meanwhile, reviews on DMD and mitochondria have mostly focused on calcium homeostasis [102] or the key interactions between mitochondrial autophagy and inflammation [99]. In contrast, a review of the literature regarding MQC mechanisms within the context of MG is currently unavailable. As a result, the present review provides a novel synthesis of data regarding MQC mechanisms and NMDs. Notably, it summarizes and describes the role of MQC processes such as mitochondrial dynamics, mitophagy, and mitochondrial biogenesis in the pathology of NMDs.

Finally, based on the existing literature, this review suggests that ginsenoside Rg1 may act as an effective active agent for targeting MQC for the management of three key neuromuscular disorders — MG, DMD, and ALS — thereby addressing existing gaps in the field. Given the critical role of MQC dysregulation in the pathogenesis of these three conditions, the ability of ginsenoside Rg1 to modulate mitochondrial biogenesis, dynamics, mitophagy, and mitocytosis offers a targeted approach to potentially treat all of these NMDs. By expounding on this crucial topic, this review offers a robust theoretical foundation for further research into the clinical relevance of ginsenoside Rg1. Ultimately, this work paves the way for potential mitochondria-targeting therapeutic strategies for NMDs, especially MG, DMD, and ALS, enhancing the understanding of Rg1's mechanisms and highlighting its broader clinical value. Abbreviations used in this article are listed in Table 6.

Table 6.

Summary of abbreviations.

Abbreviations
ACO2	aconitase	Mfn2	Mitofusin-2
AMPK	AMP-activated protein kinase	MFF	Mitochondrial Fission Factor
ALS	amyotrophic lateral sclerosis	mTOR	mammalian target of rapamycin
ALS-FTD	ALS-frontotemporal dementia	MG	myasthenia gravis
AS-IV	astragaloside IV	m6A	N6-methyladenosine
CaMKII	Ca2+/calmodulin kinase	NDUFC2	NADH dehydrogenase ubiquinone oxidoreductase subunit C2
CPTII	carnitine palmitoyl transferase II	NMDs	Neuromuscular diseases
CHCHD10	coiled-coil-helix-coiled-coil-helix domain containing 10	Nrf1	nuclear respiratory factor 1
CYCS	cytochrome C	OPA1	optic atrophy protein-1
C9ORF72	chromosome 9 open reading frame 72	OPTN	optineurin
Drp1	dynamin-related protein 1	OXPHOS	oxidative phosphorylation
DMD	Duchenne muscular dystrophy	PBMCs	peripheral blood mononuclear cells
EAMG	experimental autoimmune myasthenia gravis	PHB	prohibitin
ECHS1	enoyl-CoA hydratase	PINK1	PTEN-induced putative kinase 1
Fis1	Mitochondrial Fission 1 protein	PT	pterostilbene
FBXO3	F-Box Protein 3	PGC-1α	peroxisome proliferator-activated receptor gamma coactivator-1α
FUNDC1	FUN14 domain-containing protein 1	SOD1	copper-zinc superoxide dismutase
GSTP1	Glutathione S-transferase pi	SIRT1	Sirtuin 1
IDE	idebenone	SQSTM1	sequestosome-1
LCDA	long-chain dicarboxylic acid	TBK1	TANK-binding kinase 1
LC3	microtubule-associated protein 1 A/1 B-light chain 3	TCA	Tricarboxylic acid cycle
LEDT	light-emitting diode therapy	TFAM	mitochondrial transcription factor A
LPS	lipopolysaccharide	ULK1	UNC51-like kinase-1
MQC	mitochondrial quality control	UA	urolithin A
MDH2	malate dehydrogenase 2	UBQLN2	ubiquilin 2
MMP	mitochondrial membrane potential	YTHDF1	YTH N6-methyladenosine RNA binding protein 1
Mfn1	Mitofusin-1

Funding

This work was supported by the National Natural Science Foundation of China (82374391), the Natural Science Foundation of Guangdong Province (2023A1515011127) and the Project in Key Fields of Universities in Guangdong Province (2021ZdZX2032).

Declaration of competing interest

The authors declare no conflict of interest.