mitophagy

Overview

Mitophagy is a highly selective form of autophagy in which damaged, dysfunctional, or superfluous mitochondria are sequestered within double-membrane vesicles called mitophagosomes and delivered to lysosomes for enzymatic degradation. As a cornerstone of mitochondrial quality control (MQC), mitophagy functions as a cellular surveillance mechanism that prevents the accumulation of depolarized or reactive oxygen species (ROS)-generating mitochondria, thereby preserving energy metabolism, redox homeostasis, and overall cell viability. The most extensively characterized pathway is the PINK1–Parkin axis, in which the serine/threonine kinase PINK1 accumulates on the outer membrane of damaged mitochondria (those with dissipated mitochondrial membrane potential) and recruits the E3 ubiquitin ligase Parkin, triggering ubiquitin-mediated cargo recognition and autophagosome formation. Additional receptor-mediated pathways, such as those involving BNIP3 and NIX, operate independently of Parkin and respond to hypoxic or developmental signals. Collectively, these pathways regulate the selective elimination of damaged mitochondria and maintain mitochondrial homeostasis within the cell.

Beyond its housekeeping role, mitophagy is tightly integrated with broader cellular stress-response pathways, influencing oxidative stress, inflammation, cellular senescence, and cell fate decisions including apoptosis and ferroptosis. Disruption of mitophagy—whether through impaired initiation, blocked autophagosome–lysosome fusion, or lysosomal dysfunction—underlies the pathogenesis of a wide spectrum of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular conditions, and pulmonary injury. Conversely, excessive or dysregulated mitophagy can itself drive pathological outcomes, underscoring its fundamentally dual role in health and disease.

Focus of Latest Publications

Neurodegenerative Diseases

Mitophagy has emerged as a central mechanistic axis in multiple neurodegenerative diseases. In Parkinson's disease (PD), the PINK1–Parkin-mediated mitophagy pathway has been characterized as a critical neuroprotective quality-control system that eliminates damaged mitochondria from dopaminergic neurons. A recent study analyzing the OMA1–DELE1–HRI axis alongside PINK1–Parkin signaling highlighted how these parallel stress-response pathways cooperate or compete to regulate mitochondrial fate in PD neurons. Separately, sulforaphane—a hydrogen sulfide (H₂S) donor—was shown to activate mitophagy in both in vitro and in vivo Parkinson's disease models, leading to clearance of damaged mitochondria and reduction of mitochondrial-derived reactive oxygen species (mtROS), while also suppressing NLRP3 inflammasome activation. DPP-4 inhibitors sitagliptin and vildagliptin were reported to engage multi-target networks modulating autophagy and mitophagy to facilitate clearance of pathogenic protein aggregates and dysfunctional mitochondria in PD models.

In Alzheimer's disease (AD), defective mitophagy has been mechanistically linked to mitochondrial dysfunction, neuroinflammation, energy deprivation, synaptic loss, and cognitive decline. The natural compound ajugol was found to ameliorate mitochondrial dysfunction and cognitive impairment in AD models through BNIP3-dependent mitophagy. Ghrelin was reported to enhance mitophagy—evidenced by increased LC3II/I and Parkin levels—while inhibiting autophagosome formation and suppressing inflammation in AD-associated astrocyte dysfunction, an effect mediated through UCP2-dependent inhibition of FOXO1 nuclear translocation. The interplay between mitophagy and ferroptosis, an iron-dependent form of regulated cell death, has been identified as a self-amplifying loop that drives neurodegeneration in AD, with SQSTM1 (p62) serving as a molecular link between these pathways. Additionally, human in vitro and rodent in vivo studies modeling cerebral amyloidosis demonstrated disrupted mitophagy—evidenced by reduced localization of TOMM20 to lysosomes—as an early event upstream of amyloid pathology involving Beta amyloid and microtubule associated protein tau.

Kidney Disease

Diabetic kidney disease (DKD) and chronic renal insufficiency have been the focus of substantial mitophagy research. Impaired mitophagy is identified as one of several converging mechanisms of mitochondrial dysfunction in diabetic kidneys, alongside excessive production of mitochondrial reactive oxygen species and reduced mitochondrial biogenesis. The metalloprotease ADAMTS13 was reported to alleviate diabetic nephropathy by modulating ferroptosis through regulation of mitophagy, involving the Nrf2/GPX4/eNOS signaling pathway and amelioration of endothelial dysfunction. The nuclear factor erythroid 2-related factor 2 (Nrf2)–GPX4 axis thus connects mitophagy to iron metabolism and lipid peroxidation in the diabetic kidney. In chronic kidney disease, the herbal formulation QingShen Granules was found to activate mitophagy to suppress renal tubular epithelial-to-mesenchymal transition via the miR-23b-5p/Nrf2/PINK1 axis, establishing a regulatory hierarchy from non-coding RNA to mitophagy induction. SOGA1 knockdown using sh-SOGA1 technology was shown to alleviate non-alcoholic steatohepatitis (NASH) progression by reducing hepatocyte senescence through activation of the AMPK/mechanistic target of rapamycin kinase pathway, which restored mitophagy and mitochondrial homeostasis and reversed cellular senescence driven by damaged mitochondria.

Cardiovascular Disease

Multi-omics profiling of human myocardium from diabetic patients revealed coupled dysregulation of lipid metabolism, mitophagy, and extracellular matrix remodeling as interlocking pathological features of the diabetic heart. A dedicated review of autophagy and mitophagy in cardiomyopathy characterized the dual role of mitochondrial autophagy—protective under basal conditions and potentially maladaptive during sustained cardiac stress—with proper mitophagy being indispensable for maintaining cardiac function. In Friedreich's ataxia, mitochondrial iron overload was associated with lysosomal dysfunction that impaired mitophagy, resulting in excessive accumulation of the autophagy receptor proteins p62 (SQSTM1) and Parkin and a paradoxical increase in dysfunctional mitochondria despite elevated mitochondrial biogenesis.

Pulmonary Disease and Acute Injury

Near-infrared light-activated palladium-loaded carbon quantum dots derived from Siraitia grosvenorii were developed as a nanomaterial platform that amplifies mitophagy to selectively eliminate dysfunctional mitochondria in acute lung injury, providing immunotherapeutic benefit. Kinetin, a plant cytokinin, activated mitophagy in macrophages to mitigate coal-silica mixed dust-induced pulmonary fibrosis by modulating macrophage mitochondrial function and reducing oxidative stress in mice. A mitochondria-targeted co-assembled nanosystem upregulated mitophagy to selectively eliminate damaged mitochondria and alleviate inflammation while promoting chronic wound healing, including in the context of diabetic foot ulcer treatment with hydrogen-enriched hyaluronic acid dressings that promoted mitophagy as a therapeutic mechanism.

Metabolic and Musculoskeletal Disease

Dysregulated mitophagy coupled with osteoclast activation has been implicated in the development and progression of osteoporosis. Albiflorin was reported to alleviate osteoporosis by suppressing osteoclast mitophagy via the Rap1a/ERK signaling pathway. In acute gouty arthritis, RGFP966 inhibited AIM2 inflammasome activation to promote mitophagy, identifying inflammasome–mitophagy crosstalk as a therapeutic target. In senescence biology, impaired mitophagy was identified as a significant contributor to cellular senescence and reduced proliferative capacity of human adipose-derived mesenchymal stem cells; melatonin and ubidecarenone (Coenzyme Q10) were found to mitigate senescence by restoring mitophagy and mitochondrial proteostasis.

Viral and Skeletal Biology

An unexpected role for mitophagy in viral biology was uncovered when enterovirus-induced cleavage of Mitofusin 2 was shown to generate mitophagosomes—hallmarks of mitophagy—that are co-opted for enveloped virion release, revealing that pathogens can hijack the mitophagy machinery for replication. In skeletal aging, excessive mitophagy and cell senescence were identified as downstream consequences of periosteal mitochondrial DNA structural abnormalities that drive aging-associated impairment of bone repair. A concern was also raised regarding a study on intracerebral hemorrhage, in which electroacupuncture at GV20–GB7 was reported to regulate mitophagy to protect against neurological deficits via inhibition of apoptosis involving AKT serine/threonine kinase 1 and TP53 signaling.

Nanomaterial-Mediated Regulation

A growing body of work examines how nanomaterials regulate cellular functions and influence cell fate through mitophagy. carbon quantum dots and palladium-based nanomaterials have been shown to amplify mitophagy, while mitochondria-targeted nanosystems leverage controlled mitophagy induction to modulate redox homeostasis, reduce proinflammatory cytokine release, and direct cell fate, establishing mitophagy as a targetable node in nanomedicine.