PXD047765

PXD047765 is an original dataset announced via ProteomeXchange.

Title	Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress
Description	Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early onset Parkinson disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane (OMM) forming a high molecular weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates ubiquitin, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved, remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress, such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 NT-CTE module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.
HostingRepository	PRIDE
AnnounceDate	2024-03-02
AnnouncementXML	Submission_2024-03-02_13:50:19.884.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andrew Bayne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-12 11:20:08	ID requested
⏵ 1	2024-03-02 13:50:20	announced

10.1073/pnas.2313540121;

Eldeeb MA, Bayne AN, Fallahi A, Goiran T, MacDougall EJ, Soumbasis A, Zorca CE, Tabah JJ, Thomas RA, Karpilovsky N, Mathur M, Durcan TM, Trempe JF, Fon EA, Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress. Proc Natl Acad Sci U S A, 121(10):e2313540121(2024) [pubmed]

submitter keyword: PINK1, human, TOM complex, mitochondria, TIM complex, Parkinson's

Jean-Francois Trempe
contact affiliation	1. Department of Pharmacology & Therapeutics, McGill University, Montréal, Québec, Canada 2. Centre de Recherche en Biologie Structurale, Montréal, Québec, Canada
contact email	jeanfrancois.trempe@mcgill.ca
lab head
Andrew Bayne
contact affiliation	McGill University
contact email	andrew.bayne@mail.mcgill.ca
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/03/PXD047765

PRIDE project URI

• PRIDE
  1. PXD047765
     1. Label: PRIDE project
     2. Name: Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress