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Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles

Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles
Tollip coordinates Parkin-dependent trafficking of mitochondrial-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 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.

Parkinson's disease, lysosome, membrane trafficking, mitochondria, vesicle transport
0261-4189
Ryan, Thomas A
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Phillips, Elliott O
cb1f0c34-488a-412a-9af6-ed9fa483ed43
Collier, Charlotte L
f2661886-8e4c-46bf-a4b7-01e05c3347b3
Robinson, Alice J B
ff4c029a-9924-4c79-9ff4-4b5f21e78b06
Routledge, Daniel
de0c5011-a5c9-49e3-b131-ca2729f2d162
Wood, Rebecca E
30c0e9e3-a1d9-4988-a7c8-1fda7307a214
Assar, Emelia A
95c06484-59ca-4cfb-a818-4d4ad7d0ea77
Tumbarello, David A
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Ryan, Thomas A
ea35c378-0f6e-4ea0-8a55-2a8703d85412
Phillips, Elliott O
cb1f0c34-488a-412a-9af6-ed9fa483ed43
Collier, Charlotte L
f2661886-8e4c-46bf-a4b7-01e05c3347b3
Robinson, Alice J B
ff4c029a-9924-4c79-9ff4-4b5f21e78b06
Routledge, Daniel
de0c5011-a5c9-49e3-b131-ca2729f2d162
Wood, Rebecca E
30c0e9e3-a1d9-4988-a7c8-1fda7307a214
Assar, Emelia A
95c06484-59ca-4cfb-a818-4d4ad7d0ea77
Tumbarello, David A
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2

Ryan, Thomas A, Phillips, Elliott O, Collier, Charlotte L, Robinson, Alice J B, Routledge, Daniel, Wood, Rebecca E, Assar, Emelia A and Tumbarello, David A (2020) Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles. The EMBO Journal, 39 (11), [e102539]. (doi:10.15252/embj.2019102539).

Record type: Article

Abstract

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.

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Ryan et al_EMBO J_Accepted version - Accepted Manuscript
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Accepted/In Press date: 10 March 2020
e-pub ahead of print date: 20 April 2020
Published date: 2 June 2020
Keywords: Parkinson's disease, lysosome, membrane trafficking, mitochondria, vesicle transport

Identifiers

Local EPrints ID: 438725
URI: http://eprints.soton.ac.uk/id/eprint/438725
ISSN: 0261-4189
PURE UUID: a957433c-7c23-445c-ad4a-9ce0b464d5cc
ORCID for David A Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561

Catalogue record

Date deposited: 23 Mar 2020 17:31
Last modified: 18 Feb 2021 17:23

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