The ERAD ubiquitin ligase Doa10 negatively regulates Atg32-mediated mitophagy

Degradation of defective or superfluous mitochondria via mitophagy, a specialized form of selective autophagy, is important for maintaining mitochondrial quality and quantity. In yeast, the pro-mitophagic factor Atg32 is transcriptionally upregulated upon oxidative stress and anchored to the mitochondrial surface, where it acts as a molecular signal to initiate efficient degradation of mitochondria. However, how the protein levels of Atg32 are regulated post-translationally remains enigmatic. Here we show that the endoplasmic reticulum (ER) serves as a hub to govern Atg32 protein turnover. We found that the ER-associated degradation (ERAD) E3 ligase Doa10 interacts with Atg32, leading to its degradation by the proteasome. Furthermore, we show that Atg32 is destined for the ER in a manner dependent on the GET (guided entry of tail-anchored proteins) pathway, which mediates the delivery of tail-anchored (TA) proteins to the ER where Atg32 is potentially recognized by Doa10. Notably, Doa10 deficiency increased Atg32 levels and enhanced mitophagy under respiratory conditions, thus determining that ERAD serves as a brake on mitophagy.