Fig 1.
PINK1–Parkin-dependent mitophagy is crucial for dopaminergic neuron viability.
(A) In healthy mitochondria with a polarized mitochondrial membrane potential (ψm), PINK1 is cleaved by PARL on the inner mitochondrial membrane rendering it vulnerable to proteosome degradation. Upon mitochondrial membrane depolarization, PINK1 is instead stabilized at the outer mitochondrial membrane where it phosphorylates ubiquitin molecules (pUb(Ser65)). pUb(Ser65) serves as a recruitment site for Parkin, which is subsequently phosphorylated by PINK1 to activate it. Parkin deposits further ubiquitin chains at the mitochondria, which are also phosphorylated by PINK1, resulting in a positive feedback loop resulting in the coating of damaged mitochondria with pUb(Ser65). pUb(Ser65) serves as a signal for autophagosome formation, engulfment, and subsequent degradation of the damaged mitochondria through the autophagy–lysosome pathway. Kinetins serve as potent neosubstrates for PINK1 and can enhance PINK1-dependent activity, while inhibitors of the deubiquitinase USP30 can enhance mitochondrial ubiquitination. (B) Dopamine metabolism is associated with high levels of ROS production (e.g., mitochondrial MAOA catabolism of dopamine) rendering dopaminergic neurons particularly vulnerable to oxidative damage. Impairments in PINK1 or Parkin can result in the accumulation of damaged mitochondria, which release ROS and toxins that target OXPHOS complex I elevate mitochondria-derived ROS production. PINK1 and Parkin are also involved in attenuating release of MDVs for MitoAP and activation of adaptive immune responses. Finally, PINK1and Parkin prevent uncontrolled release of mtDNA by damaged mitochondria, which would otherwise activate the cGAS–STING pathway resulting in activation of type I IFN-mediated innate immune responses. IFN, interferon; MAOA, monoamine oxidase-A; MDV, mitochondria-derived vesicle; MitoAP, mitochondrial antigen presentation; ROS, reactive oxygen species.