PXD047774

PXD047774 is an original dataset announced via ProteomeXchange.

Title	Impaired protein import drives mitochondrial dysfunction upon mutation of TIMM50 in mitochondrial disease
Description	TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of presequence-containing precursors into the matrix or inner membrane. Here we describe a mitochondrial disease patient that is homozygous for a novel variant in TIMM50 and establish the first proteomic profile of mitochondrial disease associated with TIMM50 mutation. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient cells and a TIMM50 HEK293T cell model of disease, we reveal that laterally inserted substrates imported via the TIM23SORT complex are more sensitive to loss of TIMM50. Indeed, proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in laterally-released TIM23SORT substrates, providing a biochemical mechanism for the specific defects in TIMM50 patients. These results highlight the power of using proteomics for elucidating molecular mechanisms of disease and uncovering novel features of fundamental biology.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:48:44.414.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jordan Crameri
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-12 18:55:37	ID requested
1	2024-07-03 02:49:51	announced
⏵ 2	2024-10-22 06:48:45	announced	2024-10-22: Updated project metadata.

10.1080/10985549.2024.2353652;

Crameri JJ, Palmer CS, Stait T, Jackson TD, Lynch M, Sinclair A, Frajman LE, Compton AG, Coman D, Thorburn DR, Frazier AE, Stojanovski D, Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease. Mol Cell Biol, 44(6):226-244(2024) [pubmed]

submitter keyword: Mitochondrial Protein Import, TIM23 Complex,Mitochondria, TIMM50, Mitochondrial Disease

Diana Stojanovski
contact affiliation	Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, 3052, Australia
contact email	d.stojanovski@unimelb.edu.au
lab head
Jordan Crameri
contact affiliation	The University of Melbourne
contact email	cramerij@student.unimelb.edu.au
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/2024/07/PXD047774

PRIDE project URI

• PRIDE
  1. PXD047774
     1. Label: PRIDE project
     2. Name: Impaired protein import drives mitochondrial dysfunction upon mutation of TIMM50 in mitochondrial disease