Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases

The selective clearance of unwanted, damaged or dangerous components by macroautophagy/autophagy is critical for maintaining cellular homeostasis in organisms from yeast to humans. In recent years, significant progress has been made in understanding how phagophores selectively sequester specific cargo. Nevertheless, a fundamental question remains: Can distinct selective autophagy programs simultaneously operate within the same cell? A recent study from the Baehrecke lab has unveiled a developmentally programmed Pink1-dependent reticulophagy process in the Drosophila intestine. Furthermore, this study demonstrated that autophagy differentially clears mitochondria and ER in the same cell under the regulation of Pink1 through different E3 ubiquitin ligases, highlighting the need for further exploration in understanding the complexity of autophagic substrate selection and crosstalk between diverse autophagy programs.