Figure 1.

MARCH5 plays a role in mitochondrial morphology and mitophagy. In the mitochondrial dynamic machinery, MARCH5 suppresses mitochondrial fission by ubiquitinating DNM1L or decreasing DNM1L translocation to mitochondria by ubiquitinating and degrading fission receptors FIS1 and MIEF2. In the mitophagy machinery, initial hypoxic stress induces disassembly of MARCH5 oligomers and enhances the interaction of MARCH5 with the mitophagy receptor FUNDC1, which induces ubiquitination and degradation of FUNDC1. Degradation of FUNDC1 conversely inhibits initiation of mitophagy, thus circumventing inappropriate removal of mitochondria. As the exposure time of hypoxia mounts up, FUNDC1 is dephosphorylated and mitophagic flux rapidly increases, thereby recruiting more phagophores to damaged mitochondria for removal.