Parkin coordinates mitochondrial lipid remodeling to execute mitophagy

Abstract

AbstractMitochondrial failure caused by Parkin mutations contributes to Parkinson’s disease. Parkin binds, ubiquitinates, and targets impaired mitochondria for autophagic destruction. Robust mitophagy involves peri-nuclear concentration of Parkin-tagged mitochondria, followed by dissemination of juxtanuclear mitochondrial aggregates, and efficient sequestration of individualized mitochondria by autophagosomes. Here, we report that the execution of complex mitophagic events requires active mitochondrial lipid remodeling. Parkin recruits phospholipase D2 to the depolarized mitochondria and generate phosphatidic acid (PA). Mitochondrial PA is subsequently converted to diacylglycerol (DAG) by Lipin-1 phosphatase-a process that further requires mitochondrial ubiquitination and ubiquitin-binding autophagic receptors, NDP52 and Optineurin. We show that Optineurin transports, via Golgi-derived vesicles, a PA-binding factor EndoB1 to ubiquitinated mitochondria, thereby facilitating DAG production. Mitochondrial DAG activates both F-actin assembly to drive mitochondrial individualization, and autophagosome biogenesis to efficiently restrict impaired mitochondria. Thus Parkin, autophagic receptors and the Golgi complex orchestrate mitochondrial lipid remodeling to execute robust mitophagy.