Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts

MTCH2 acts as a novel inhibitory receptor to suppress germ cell mitophagy by tethering BECN1, thereby maintaining mitochondrial homeostasis and male fertility

Mitochondria play a pivotal role in spermatogenesis and male fertility, in which the selective autophagic degradation of mitochondria (mitophagy) constitutes a key process. In this study, we identify mitochondrial carrier homolog 2 (MTCH2) as a novel and critical regulator of germ cell mitophagy. Localized to the mitochondrial outer membrane (OMM), MTCH2 directly interacts with the core autophagy protein BECN1, thereby inhibiting autophagic flux and specifically suppressing mitophagy. Germ cell-specific heterozygous deletion of Mtch2 was sufficient to cause profound spermatogenic defects, including disorganized seminiferous tubules, vacuolization, mitochondrial sheath abnormalities, and significantly impaired sperm fertilization capacity. Transcriptomic profiling revealed that MTCH2 deficiency dysregulates pathways central to mitochondrial function and programmed cell death. Importantly, augmenting autophagy ameliorated mitochondrial dysfunction induced by MTCH2 deficiency, as characterized by impaired mitochondrial membrane potential, elevated mitochondrial reactive oxygen species (mtROS) production and cellular ROS levels. Collectively, our findings establish MTCH2 as an essential negative regulator of mitophagy that partners with BECN1 to maintain mitochondrial homeostasis, thereby ensuring normal spermatogenesis and male fertility.

Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.

Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver disorder globally, with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis. Mitochondrial dysfunction is central to MASLD progression, and mitophagy-a selective form of autophagy that clears damaged mitochondria-plays a crucial role in maintaining cellular homeostasis. This review systematically delineates the molecular mechanisms, regulatory networks, and therapeutic implications of mitophagy in MASLD. We first outline the core machinery of mitophagy, encompassing both ubiquitin-dependent and ubiquitin-independent pathways. We then discuss how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types. Furthermore, we summarize the multilayered upstream regulatory network governing mitophagy in the context of MASLD, involving key signaling pathways, metabolic reprogramming, inflammatory cues, epigenetic modifications, and intercellular crosstalk. Finally, we examine therapeutic strategies targeting mitophagy-including clinical and preclinical agents, natural compounds, physical interventions, and emerging technologies-and highlight the challenges posed by its dualistic nature. Moving forward, integrating spatiotemporal dynamics with precision targeting will be essential to translate mitophagy modulation from mechanistic insight into viable clinical therapies for MASLD.

Regulation and roles of mammalian mitophagy.

Differential Regulation of Mitochondrial and Autophagy Markers in a Mouse Model of Cardioskeletal Myopathy

These findings reveal pronounced tissue divergence in mitochondrial remodeling in DARS2-related cardioskeletal myopathy and underscore caution when interpreting colchicine-based autophagy flux assays in heart versus skeletal muscle.

Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.

Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.

Molecular Mechanisms Underlying FCCP-Induced Mitophagy in Human Airway Smooth Muscle Cells

Mitophagy is a selective autophagic process that eliminates damaged mitochondria, which is essential for mitochondrial quality control and cellular homeostasis. The most extensively characterized mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane (OMM), where it recruits and phosphorylates Parkin at serine 65 (pParkinS65), activating its E3 ligase activity. Active pParkinS65 initiates the ubiquitination (Ub) of OMM proteins resulting in the engulfment and lysosomal degradation of damaged (depolarized) mitochondria. Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial uncoupler, is widely used to experimentally induce mitochondrial depolarization and initiate PINK1-Parkin-dependent mitophagy; however, mitophagic responses to FCCP vary across cell types. In the present study, we hypothesized that, in human airway smooth muscle (hASM) cells, FCCP-induced mitochondrial depolarization activates the PINK1-Parkin-mediated mitophagy pathway, culminating in the clearance of damaged mitochondria. We observed that exposing hASM cells to 1 μM FCCP for 6 h induced mitochondrial depolarization and a decrease in the volume of intact mitochondria. This mitochondrial depolarization triggered the accumulation of PINK1 in the mitochondria, which mediated phosphorylation of pParkinS65 and an increase in pUbS65 proteins. Confocal imaging of labeled mitochondria and lysosomes demonstrated increased colocalization of mitochondria with lysosomes, and mitophagic flux was confirmed using a pH-sensitive mitochondrial reporter mKeima. Collectively, these findings demonstrate that FCCP robustly activates the canonical PINK1-Parkin mitophagy pathway in hASM cells, providing mechanistic insight into mitochondrial quality control, with potential relevance to airway diseases characterized by mitochondrial dysfunction and altered hASM function.