Tollip coordinates Parkin-dependent trafficking of mitochondria-derived vesicles

Multiple mitochondrial quality control pathways exist to maintain the health of mitochondria and ensure cell homeostasis. Here we investigate the role of the endosomal adaptor Tollip during mitochondrial stress response and identify its interaction and colocalisation with the Parkinson's disease associated E3 ubiquitin ligase Parkin. The interaction between Tollip and Parkin is dependent on the ubiquitin-binding CUE domain of Tollip, but independent of Tom1 and mitophagy. Interestingly, this interaction is independent of Parkin mitochondrial recruitment and ligase activity but requires an intact Ubiquitin-like (UBL) domain. Importantly, Tollip regulates Parkin-dependent endocytic trafficking of a discrete subset of mitochondria-derived vesicles to facilitate their lysosomal disposal. Retromer function and binding to Tom1 allow Tollip to facilitate late endosome/lysosome trafficking in response to mitochondrial stress. We find that upregulation of TOM20-positive MDVs upon mitochondrial stress requires Tollip interaction with ubiquitin, endosomal membranes, and Tom1 to ensure their trafficking to the lysosomes. Thus, we conclude that Tollip, via an association with Parkin, is an essential coordinator to sort damaged mitochondrial-derived cargo to the lysosomes.