SNX10 at the crossroad of endocytosis and piecemeal mitophagy

Abstract

Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.

Keywords: SNX10; endosomal sorting; mitophagy; oxidative stress; zebrafish.

Figure 1.

SNX10 modulates piecemeal mitophagy. SNX10 localizes to early endosomes via the binding of its PX domain to PI(3)P. Additionally, SNX10 localizes to late endosomes and was found to promote the trafficking of the EGFR in control conditions. Under hypoxia-mimicking conditions (using DFP or DMOG), SNX10-positive late endosomes co-occur with LC3 and incorporate selective mitochondrial components recognized by p62. SNX10 was found to inhibit the turnover of selected mitochondrial proteins, including COX-IV, indicating a role for SNX10 in piecemeal mitophagy. In vivo, zebrafish larvae lacking Snx10 (snx10ab double knock-out (DKO)) are characterized by increased levels of reactive oxygen species (ROS) and ROS-mediated cell death, as shown by increased TUNEL staining. Created in BioRender. Simonsen, A. (2025) https://BioRender.com/efesd4g.