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.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMFR/GP78: autocrine motility factor receptor; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATG: autophagy related; Aβ: amyloid beta; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMc: core autophagy machinery components; CSNK2/CK2: casein kinase 2; DUB: deubiquitinase; DNM1L/DRP1: dynamin 1 like; FKBP8: FKBP prolyl isomerase 8; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GLP-1: glucagon-like peptide 1; HD: Huntington disease; HUWE1: HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1; IMM: inner mitochondrial membrane; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCHF5: membrane associated ring-CH-type finger 5; MCL1: MCL1 apoptosis regulator, BCL2 family member; MDV: mitochondria-derived vesicle; MFN1: mitofusin 1; MFN2: mitofusin 2; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; OMM: outer mitochondrial membrane; OMMAD: outer mitochondrial membrane-associated degradation; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; OXPHOS: oxidative phosphorylation; PARL: presenilin associated rhomboid like; PD: Parkinson disease; PE: phosphatidylethanolamine; PG: phagophore; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PINK1: PTEN induced kinase 1; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RHOT1/Miro1: ras homolog family member T1; ROS: reactive oxygen species; SIAH1: siah E3 ubiquitin protein ligase 1; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TCA: tricarboxylic acid cycle; TFAM: transcription factor A, mitochondrial; TIMM: translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UPRmt: mitochondrial unfolded protein response; UPS: ubiquitin-proteasome system; USP30: ubiquitin specific peptidase 30; VCP: valosin containing protein; VDAC: voltage dependent anion channel; WIPI: WD repeat domain, phosphoinositide interacting.