KAT8 compound inhibition inhibits PINK1/Parkin-dependent mitophagy and initiates mitochondrial delivery to lysosomes

Abstract It has recently been shown that KAT8 , a genome-wide association study (GWAS) candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependent mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal (NSL) epigenetic remodeling complex. In the current study, we showed that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibited the initial steps of the PINK1-dependant mitophagy process. More specifically, our study showed that MG149 inhibited PINK1-dependent mitophagy initiation by impairing PINK1-autophosphorylation and activation, thus preventing phosphorylation of Parkin and ubiquitin. While preventing PINK1-dependent mitophagy initiation, MG149 promoted the downstream recruitment of the autophagy receptor p62 and initiated mitochondrial delivery to the lysosomes independently of PINK1. Altogether, our study provided additional support for KAT8 inhibition as a regulator of mitophagy and autophagy processes.