Mitophagy pathway (PINK1-Parkin-dependent and independent) (Mitophagy)

Mitophagy is the selective degradation of damaged or redundant mitochondria via the autophagy-lysosomal pathway, serving as a critical mechanism for mitochondrial quality control and cellular homeostasis [1, 2]. The PINK1-Parkin-dependent pathway is the most extensively studied, involving the accumulation of PTEN-induced kinase 1 (PINK1) on the outer mitochondrial membrane of depolarized mitochondria, which subsequently recruits and activates the E3 ubiquitin ligase Parkin [2, 3]. Parkin then ubiquitinates various mitochondrial proteins, signaling for autophagosomal engulfment. Conversely, PINK1-Parkin-independent mitophagy is mediated by specific receptors such as BNIP3, NIX, and FUNDC1, which contain LC3-interacting regions (LIR) to directly recruit autophagosomes to the mitochondria [3, 4]. Impairment of these pathways is a hallmark of neurodegenerative diseases, most notably Parkinson's disease, where mutations in PINK1 and PRKN (Parkin) lead to the accumulation of dysfunctional mitochondria and neuronal death [5]. Therapeutic interventions targeting this pathway include the development of PINK1 activators, Parkin activators, and inhibitors of USP30, a deubiquitinating enzyme that opposes Parkin-mediated mitophagy [6, 7].

Other names

Mitochondrial autophagyPINK1-PRKN pathwayReceptor-mediated mitophagyMitochondrial quality control

Activation of PINK1 or Parkin, or inhibition of USP30 to promote the clearance of damaged mitochondria.