The Emerging Role of Proteolysis in Mitochondrial Quality Control and the Etiology of Parkinson’s Disease

Figure 3

The PINK1/Parkin pathway mediates mitochondrial elimination via mitophagy. Accumulation of ROS and other toxic molecules can damage mitochondria, resulting in the loss of mitochondrial membrane potential and eventually the reduction in mitochondrial ATP concentration. Loss of mitochondrial membrane potential triggers the accumulation of PTEN-induced kinase 1 (PINK1) on the mitochondrial outer membrane (OMM). The accumulation of PINK1 recruits the cytoplasmic E3 ubiquitin ligase, Parkin, to the damaged mitochondria. The mechanism of this recruitment is still unclear; however, several models have been proposed, in which the substrates shared by PINK1 and Parkin may play a role in mediating their interaction. Once on the mitochondria, Parkin ubiquitinates various OMM proteins, including the mitochondrial profusion protein, mitofusin 1. Polyubiquitin chains on these proteins serve as a signal for the recruitment of the autophagosome that engulfs and degrades the damaged mitochondrion through a process called mitophagy.