Mitophagy and mitochondrial fission pathways

Mitophagy and mitochondrial fission pathways are integrated cellular processes essential for mitochondrial quality control (MQC) and the maintenance of cellular bioenergetics. Mitochondrial fission, primarily mediated by the recruitment of the GTPase Dynamin-related protein 1 (DRP1) to the outer mitochondrial membrane, facilitates the division of the mitochondrial network into smaller fragments (Youle & van der Bliek, 2012, Science). This fragmentation is often a prerequisite for mitophagy, the selective autophagic degradation of damaged or redundant mitochondria, which is frequently regulated by the PINK1/Parkin signaling axis or specific mitophagy receptors such as BNIP3 and NIX (Narendra et al., 2008, J Cell Biol; Novak et al., 2010, EMBO Rep). Dysregulation of these pathways leads to the accumulation of dysfunctional mitochondria and oxidative stress, which are central to the pathogenesis of neurodegenerative diseases like Parkinson's and Alzheimer's, as well as cardiovascular and metabolic disorders (Pickrell & Youle, 2015, Neuron). Therapeutic strategies targeting these pathways include DRP1 inhibitors like Mdivi-1 to prevent excessive fission and mitophagy inducers like Urolithin A to enhance the clearance of damaged organelles (Cassidy-Stone et al., 2008, Dev Cell; Andreux et al., 2019, Nature Metabolism). However, the development of such therapies faces challenges due to the ubiquitous nature of mitochondria and the potential for systemic toxicity if basal mitochondrial dynamics are disrupted (Archer, 2013, NEJM).

Other names

Mitochondrial quality controlMitophagy-fission axisMitochondrial dynamics

Pharmacological modulation involves the inhibition of mitochondrial fission proteins like DRP1 to prevent fragmentation-induced cell death, or the activation of mitophagy-related proteins (e.g., PINK1, Parkin, or AMPK) to promote the clearance of damaged mitochondria (Youle & van der Bliek, 2012, Science; Andreux et al., 2019, Nature Metabolism).