SNX10 regulates the clearance of mitochondrial proteins and mitochondrial bioenergetics

Abstract

ABSTRACTWe here show that SNX10 localizes to endocytic compartments in a PtdIns3P-dependent manner and that mutations in the PX domain associated with autosomal recessive osteopetrosis prevent its endosomal recruitment. We demonstrate that SNX10 regulates endosomal trafficking but also interacts with mitochondrial proteins and shows dynamic interactions with mitochondria. Intriguingly, SNX10 and RAB5A-positive vesicles contain mitochondrial material and stain positive for LC3B. SNX10-positive vesicles contain COX-IV and SAMM50, both proteins being important for mitochondrial respiratory chain function, while other mitochondrial proteins are excluded. We find that depletion of SNX10 results in lower levels of COX-IV and SAMM50 both in vitro and in a zebrafish model, as well as impaired mitochondrial respiration and reduced citrate synthase activity, indicating a role for SNX10 as a regulator of mitochondrial bioenergetics. Importantly, the knockout of SNX10 homologs in zebrafish led to elevated ROS levels and cell death, demonstrating the in vivo relevance of SNX10-mediated regulation of mitochondrial homeostasis.SummaryTrachsel-Moncho et al. identify the endosomal protein SNX10 as a regulator of mitochondrial homeostasis. They show that SNX10 vesicles contain selected mitochondrial proteins and that depletion of SNX10 impairs mitochondrial respiration in cells and increases reactive oxygen species levels and cell death in vivo.