SNX10 regulates the clearance of mitochondrial proteins and mitochondrial bioenergetics

Abstract

We here identify the endosomal protein SNX10 as a negative regulator of piecemeal mitophagy of OXPHOS machinery components. In control conditions, SNX10 localizes to early endocytic compartments in a PtdIns3P-dependent manner and modulates endosomal trafficking but also shows dynamic connections with mitochondria. Upon hypoxia-mimicking conditions, SNX10 localizes to late endosomal structures containing selected mitochondrial proteins, including COX- IV and SAMM50, and the autophagy proteins SQSTM1/p62 and LC3B. The turnover of COX-IV and the ATP synthase subunit pSu9 was enhanced in SNX10-depleted cells, with a corresponding reduced mitochondrial respiration and citrate synthase activity. Importantly, zebrafish larvae lacking Snx10 show reduced levels of COX-IV, as well as elevated ROS levels and ROS-mediated cell death in the brain, demonstrating the in vivo relevance of SNX10-mediated modulation of mitochondrial bioenergetics. eTOC summaryTrachsel-Moncho et al. identify the endosomal protein SNX10 as a modulator of piecemeal mitophagy of OXPHOS machinery components and mitochondrial homeostasis. They show that loss of SNX10 enhances mitochondrial protein degradation, reduces respiration, and increases ROS levels leading to elevated cell death in vivo.