Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitoselfphagy

Abstract Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to produce ATP to power the cell. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles, including mitochondria, to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia reshapes normal tubular mitochondria to megamitochondria by inducing wide inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we termed “megamitochondria engulfing lysosome (MMEL)”. Both megamitochondria and mature lysosome are required for MMEL. Moreover, we identified that the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL and mitochondrial proteases, which are activated by hypoxia, mediate a new mode of mitochondrial degradation, which we named “mitoselfphagy”. Unlike mitophagy, mitoselfphagy degrades mitochondrial proteins unevenly in a manner independent of the autophagosome. Additionally, mitoselfphagy increases mitochondrial ROS production. Our findings reveal a novel mode of crosstalk between mitochondria and lysosomes and uncover a new pathway of mitochondrial quality control.