Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles

Ryan, Thomas A ORCID: 0000-0002-2750-0983, Phillips, Elliott O, Collier, Charlotte L, Robinson, Alice JB, Routledge, Daniel, Wood, Rebecca E, Assar, Emelia A and Tumbarello, David A
(2020) Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles. EMBO JOURNAL, 39 (11). e102539-.

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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 the 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 endosomal trafficking of a discrete subset of mitochondrial-derived vesicles (MDVs) to facilitate delivery to lysosomes. Retromer function and an interaction with 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.

Item Type: Article
Uncontrolled Keywords: lysosome, membrane trafficking, mitochondria, Parkinson's disease, vesicle transport
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 14 Jul 2021 08:26
Last Modified: 25 Dec 2023 05:43
DOI: 10.15252/embj.2019102539
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