PINK1 signalling in neurodegenerative disease.

Abstract

PTEN-induced kinase 1 (PINK1) impacts cell health and human pathology through diverse pathways. The strict processing of full-length PINK1 on the outer mitochondrial membrane populates a cytoplasmic pool of cleaved PINK1 (cPINK1) that is constitutively degraded. However, despite rapid proteasomal clearance, cPINK1 still appears to exert quality control influence over the neuronal protein homeostasis network, including protein synthesis and degradation machineries. The cytoplasmic concentration and activity of this molecule is therefore a powerful sensor that coordinates aspects of mitochondrial and cellular health. In addition, full-length PINK1 is retained on the mitochondrial membrane following depolarisation, where it is a powerful inducer of multiple mitophagic pathways. This function is executed primarily through the phosphorylation of several ubiquitin ligases, including its most widely studied substrate Parkin. Furthermore, the phosphorylation of both pro- and anti-apoptotic proteins by mitochondrial PINK1 acts as a pro-cellular survival signal when faced with apoptotic stimuli. Through these varied roles PINK1 directly influences functions central to cell dysfunction in neurodegenerative disease.