Mitophagy and Parkinson's disease: the PINK1-parkin link

Abstract

The study of rare, inherited mutations underlying familial forms of Parkinson's disease has provided insight into the molecular mechanisms of disease pathogenesis. Mutations in these genes have been functionally linked to several key molecular pathways implicated in other neurodegenerative disorders, including mitochondrial dysfunction, protein accumulation and the autophagic-lysosomal pathway. In particular, the mitochondrial kinase PINK1 and the cytosolic E3 ubiquitin ligase parkin act in a common pathway to regulate mitochondrial function. In this review we discuss the recent evidence suggesting that the PINK1/parkin pathway also plays a critical role in the autophagic removal of damaged mitochondria-mitophagy. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.

Fig. 1

A simplified schematic of macroautophagy in mammals. (a) Activation of autophagy via ULK1/2 is induced by inhibition of the TOR pathway. (b) Autophagosome formation is regulated by the ULK1/2–ATG complex and the PI3kinase complex which includes Beclin1and Vps34. (c) During elongation and closure of the autophagosome membrane, cytosolic LC3-I is cleaved by ATG4 to produce lipidated LC3-II. (d) LC3-II is recruited to the autophagosome membrane. (e) The complete autophagosome fuses with the lysosome to enable content digestion.

Fig. 2

PINK1 and parkin in mitophagy—proposed model. Upon mitochondrial membrane depolarisation, full-length PINK1 accumulates at the outer mitochondrial membrane and NIX translocates to the mitochondria. NIX and full-length PINK1 recruit parkin to the mitochondria, which leads to parkin-dependent ubiquitination of VDAC. Ubiquitination of VDAC recruits p62 while NIX recruits GABARAP to the mitochondria. NIX binds LC3, which additionally binds p62 and depolarised mitochondria are removed via autophagy.