AI Networking Cookbook: Practical recipes for AI-assisted network automation and development
TL;DR
Current understanding of PINK1-Parkin-dependent and independent mitophagy pathways are summarized, highlighting mechanistic distinctions and coordinated regulation, as well as the expanding therapeutic potential of targeting mitophagy in disease.
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.
Ten key PTMs, including lactylation, succinylation, succinylation, SUMOylation, and S-nitrosylation, acting on core regulators such as dynamin-related protein 1(DRP1), optic atrophy 1 (OPA1), Parkin, and mitochondrial Rho GTPase 1 (MIRO1) are summarized to provide a comprehensive resource for understanding mitochondrial plasticity in health and disease.
Mitophagy is increasingly recognized as a context-dependent regulator of cardiac metabolic adaptation rather than solely as a disposal pathway for damaged mitochondria. By coupling mitochondrial turnover to substrate selection, redox control, and inflammatory signaling, mitophagy can influence fatty acid oxidation (FAO), glycolysis, and oxidative phosphorylation (OXPHOS) in cardiomyocytes, vascular endothelial cells, and immune cells. In this review, the term Mitophagy-Metabolic Rewiring Axis (MMRA) is used as an integrative conceptual framework-not as a newly discovered pathway or theory-to organize evidence for bidirectional interactions between mitophagy and metabolic remodeling. The framework comprises stress inputs, mitophagy machinery and flux, metabolic outputs, and cell- or disease-level consequences, while emphasizing that the biological effect of mitophagy depends on cell type, disease stage, and duration of activation. We critically assess the AMP-activated protein kinase (AMPK)-UNC-51-like kinase 1 (ULK1), sirtuin 3 (SIRT3)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PTEN-induced kinase 1 (PINK1)-Parkin E3 ubiquitin ligase, and hypoxia-inducible factor 1-alpha (HIF-1α)-BCL2-interacting protein 3 (BNIP3)/FUN14 domain-containing 1 (FUNDC1) modules in atherosclerosis, heart failure, and ischemia/reperfusion injury. Pharmacological, substrate-based, and exercise interventions are evaluated with particular attention to the predominantly preclinical evidence base, methodological limitations in measuring mitophagy flux, and the need for validated human biomarkers. Multi-omics and spatial approaches may improve mechanistic resolution, but clinical translation will require prospective studies that link target engagement to metabolic and cardiovascular outcomes.
Certain forms of mitochondrial impairment confer longevity, while disease-associated mitochondrial dysfunction triggers pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. To explain this connection, we test multiple candidate links between Ca2+ and mitochondrial homeostasis previously established in vitro, including mitochondrial calcium uniporter (MCU)-dependent stimulation of respiration and cytosolic pathways regulating mitochondrial dynamics. We find that MCU is dispensable for both respiration and longevity in Complex I mutants. Conversely, transcriptomic profiling and imaging reveal InsP3R impairment results in maladaptive expansion of compromised mitochondrial networks. We provide evidence that this aberrant mitochondrial expansion results from disruption of a conserved, InsP3R-dependent actin remodeling network centered on Arp2/3. Disruption of actin remodeling or autophagy mimics the mitochondrial expansion and longevity suppression of InsP3R mutants. Conversely, driving mitochondrial fragmentation ameliorates mitochondrial expansion and rescues longevity in InsP3R mutants, supporting a model in which InsP3R-dependent actin remodeling is required for segregation and clearance of mitochondria. These findings identify an inter-organelle signaling axis linking ER calcium release and cytoskeletal remodeling to adaptive mitochondrial responses associated with longevity. Mitochondrial perturbations confer longevity or disease depending on if cells successfully adapt. Here, the authors show that ER calcium signalling promotes longevity during mitochondrial stress by regulating actin-dependent mitochondrial remodeling.
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.
Although mtISR has been characterized in primary mitochondrial myopathies, secondary mitochondrial dysfunction in neuromuscular disorders suggests that mtISR-related pathways may also be activated in these conditions, and its roles in skeletal muscle pathology are discussed.
We use cookies to run the site and, with your consent, for analytics and to show ads. See our Cookie Policy.