PXD058785

PXD058785 is an original dataset announced via ProteomeXchange.

Title	Metabolic remodelling in hiPSC-derived myofibres carrying the m.3243A>G mutation
Description	Mutations in mitochondrial DNA cause severe multisystem disease, frequently associated with muscle weakness. The m.3243A>G mutation is the major cause of Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke Like episodes (MELAS). Experimental models that recapitulate the disease phenotype in vitro for disease modelling or drug screening are very limited. We have therefore generated hiPSC-derived muscle fibres with variable heteroplasmic mtDNA mutation load without significantly affecting muscle differentiation potential. The cells are excitable and show physiological characteristics of muscle fibres and show well organised myofibrillar structure. In cells carrying the m.3243A>G, the mitochondrial membrane potential and oxygen consumption were reduced in relation to the mutant load. We have shown through proteomic, phosphoproteomic, and metabolomic analyses that the m.3243A>G mutation variably affects the cell phenotype in relation to the mutant load. This variation is reflected by an increase in the NADH/NAD+ ratio, which in turns influences key nutrient-sensing pathways in the myofibres. This model enables detailed study of the impact of the mutation on cellular bioenergetics and on muscle physiology with the potential to provide a platform for drug screening.
HostingRepository	PRIDE
AnnounceDate	2025-05-26
AnnouncementXML	Submission_2025-05-25_16:21:27.929.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	riccardo zenezini chiozzi
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	2024-12-11 11:17:34	ID requested
⏵ 1	2025-05-25 16:21:28	announced

10.1016/j.stemcr.2025.102448;

Valdebenito GE, Chacko AR, Chung CY, Sheshadri P, Chi H, O'Callaghan B, Madej MJ, Houlden H, Rouse H, Morales V, Bianchi K, Tedesco FS, Pitceathly RDS, Duchen MR, G mutation. Stem Cell Reports, 20(4):102448(2025) [pubmed]

submitter keyword: mitochondria

mtDNA

mtDNA mutations

iPSC-derived myofibres

Konstantinos Thalassinos
contact affiliation	Professor of Mass Spectrometry Structural & Molecular Biology Div of Biosciences UCL
contact email	k.thalassinos@ucl.ac.uk
lab head
riccardo zenezini chiozzi
contact affiliation	UCL
contact email	r.chiozzi@ucl.ac.uk
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/2025/05/PXD058785

PRIDE project URI

• PRIDE
  1. PXD058785
     1. Label: PRIDE project
     2. Name: Metabolic remodelling in hiPSC-derived myofibres carrying the m.3243A>G mutation