Strengthening the link between mitophagy and Parkinson's disease

Abstract

This scientific commentary refers to ‘Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at 16q11.2 and MAPT H1 loci’ by Soutar et al. (https://doi.org/10.1093/brain/awac325); and ‘DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy’ by Imberechts et al. (https://doi.org/10.1093/brain/awac313).

Figure 1

Basic overview of PINK1/parkin-dependent mitophagy and the newly uncovered roles of the NSL complex and DJ-1. Mitochondrial damage and depolarization lead to stabilization of the PINK1 protein kinase on the outer mitochondrial membrane. This in turn leads to recruitment and activation of parkin, via phosphorylation of parkin and ubiquitin. This results in a feed forward activation of parkin and enhanced parkin-mediated ubiquitylation of mitochondrial outer membrane proteins. These ubiquitylation events lead to recruitment of optineurin, an autophagy receptor protein that binds directly to ubiquitin and the autophagy initiation machinery. This allows growth of the phagophore, which engulfs the damaged mitochondrion. Once the autophagosome has formed, it traffics to, and fuses with, a lysosome to form the digestive hybrid organelle termed an autolysosome. New work, discussed in the main text,^, places the NSL complex early in the pathway at the level of PINK1 gene expression; as well as DJ-1 at a later stage that is critical for optineurin recruitment.