Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import

HighlightsStructural and biochemical studies of PINK1 activation and stabilisation have captured TOM complex interactions and the formation of a PINK1–TOM–TIM supercomplex.USP30 inhibition shows promising preclinical indications.FBXL4 is a major suppressor of NIX/BNIP3-dependent mitophagy.PPTC7 scaffolds the interaction of FBXL4–SCF ligase with BNIP3 and NIX.Control of PPTC7 mitochondrial import sets the levels of BNIP3 and NIX.AbstractThe selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCFFBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.