DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy

Abstract

Loss-of-function mutations in the PRKN, PINK1 and PARK7 genes (encoding parkin, PINK1 and DJ-1, respectively) cause autosomal recessive forms of Parkinson’s disease. PINK1 and parkin jointly mediate selective autophagy of damaged mitochondria (mitophagy), but the mechanisms by which loss of DJ-1 induces Parkinson’s disease, are not well understood. Here, we investigated PINK1/parkin-mediated mitophagy in cultured human fibroblasts and iPSC-derived neurons with homozygous PARK7 mutations. We found that DJ-1 is essential for PINK1/parkin-mediated mitophagy. Loss of DJ-1 did not interfere with PINK1 or parkin activation after mitochondrial depolarization, but blocked mitophagy further downstream by inhibiting recruitment of the selective autophagy receptor optineurin to depolarized mitochondria. By contrast, starvation-induced, non-selective autophagy was not affected by loss of DJ-1. In wild-type fibroblasts and iPSC-derived dopaminergic neurons, endogenous DJ-1 translocated to depolarized mitochondria in close proximity with optineurin. DJ-1 translocation to depolarized mitochondria was dependent on PINK1 and parkin and did not require oxidation of cysteine residue 106 of DJ-1. Overexpression of DJ-1 did not rescue the mitophagy defect of PINK1- or parkin-deficient cells. These findings position DJ-1 downstream of PINK1 and parkin in the same pathway and suggest that disruption of PINK1/parkin/DJ-1-mediated mitophagy is a common pathogenic mechanism in autosomal recessive Parkinson’s disease.

Strengthening the link between mitophagy and Parkinson’s disease

“…SLRs can simultaneously bind to ubiquitin and autophagosome initiating proteins including FIP200 and the ATG8s, 3 and PINK1/parkin-dependent mitophagy is dependent on the SLRs NDP52 and optineurin. 8 In neuronal tissue, optineurin is the relevant SLR regulating mitophagy, 8 and Imberechts and colleagues 5 found that loss of DJ-1 prevented recruitment of optineurin to ubiquitylated mitochondria and hence initiation of autophagosome formation. Using elegant proximity ligation assays as well as co-immunoprecipitation, they showed that these two proteins are likely in a complex together and co-translocate to mitochondria following PINK1/parkin activation.…”

“…However, two new papers published in Brain now provide compelling evidence that mitophagy is a common mechanism involved in Parkinson's disease pathology. 4,5 In the first study, Soutar and colleagues 4 in the group of Plun-Favreau delved into the extensive pool of GWAS data, with the reasoning that some of these genes may also be involved in PINK1/parkin-dependent mitophagy. Using an innovative combination of bioinformatic techniques, the authors identified 31 open reading frames that displayed a high potential to be bone fide Parkinson's disease risk genes.…”

“…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, 4 , 5 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.…”

“…However, two new papers published in Brain now provide compelling evidence that mitophagy is a common mechanism involved in Parkinson’s disease pathology. 4 , 5 …”

“…In the second study, Imberechts and colleagues 5 in Wim Vandenberghe’s group took a more targeted approach and specifically analysed the function of DJ-1 in mitophagy. The protein DJ-1, encoded by the PARK7 gene, is mutated in rare forms of Parkinson’s disease.…”