Scientific Highlights

In this study, we described sorting nexin 10 (SNX10) as a novel modulator of piecemeal mitophagy and mitochondrial bioenergetics. SNX10 is a PX domain-containing protein that localizes to early and late endocytic compartments in a PtdIns(3)P-dependent manner where it contributes to endosomal trafficking. Under hypoxia-mimicking conditions, SNX10-positive vesicles progressively mature from early to late endosomes, selectively incorporating mitochondrial proteins and autophagic components. Selective degradation of mitochondrial proteins by mitophagy is fundamental to mitochondrial homeostasis by eliminating dysfunctional proteins and to preserve efficient energy production. We found that depletion of SNX10 enhances the turnover of proteins involved in the mitochondrial respiration and ATP production, leading to impaired mitochondrial respiration, reduced ATP-linked oxygen consumption, and decreased citrate synthase activity. Furthermore, we observed that the role of SNX10 in mitochondrial homeostasis is conserved in vivo. Zebrafish larvae lacking Snx10 exhibit elevated reactive oxygen species (ROS) production, and increased ROS-mediated cell death. In conclusion, SNX10 functions as an important link between the endosomal system and mitochondrial quality control. By modulating piecemeal mitophagy, SNX10 contributes to the maintenance of mitochondrial homeostasis and bioenergetics.