PXD036026-3

PXD036026 is an original dataset announced via ProteomeXchange.

Title	Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as novel disease mechanism
Description	Primary carnitine deficiency (PCD) is an autosomal recessive monogenic disorder caused by mutations in SLC22A5. This gene encodes for OCTN2 which transports the essential metabolite carnitine into the cell. PCD patients suffer from muscular weakness and dilated cardiomyopathy (DCM). Detailed molecular disease mechanisms remain unclear. Two OCTN2-defective human induced pluripotent stem cell lines were generated, carrying a full OCTN2-knockout and a homozygous OCTN2 (N32S) loss of function mutation. OCTN2-defective genotypes exhibited lower cardiac differentiation efficiency, lower force development and resting length in engineered heart tissue format. Force was sensitive to fatty acid-based media and associated with lipid accumulation, mitochondrial alteration, higher glucose uptake and metabolic remodelling, replicating findings in animal models. Importantly, proteomic- and single nuclear RNA sequencing analysis identified ferroptosis, an iron and lipid-dependent cell death pathway linked to fibroblast activation as a novel PCD disease mechanism. This finding paves the way for specific cardiomyopathy treatment developments.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:13:44.066.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xiaoke Yin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-12 13:20:05	ID requested
1	2023-11-01 06:21:47	announced
2	2023-11-14 09:13:47	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:13:46	announced	2024-10-22: Updated project metadata.

Loos M, Klampe B, Schulze T, Yin X, Theofilatos K, Ulmer BM, Schulz C, Behrens CS, van Bergen TD, Adami E, Maatz H, Schweizer M, Brodesser S, Skryabin BV, Rozhdestvensky TS, Bodbin S, Stathopoulou K, Christ T, Denning C, H, ü, bner N, Mayr M, Cuello F, Eschenhagen T, Hansen A, Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel mechanism. Stem Cell Reports, 18(11):2123-2137(2023) [pubmed]

10.1016/j.stemcr.2023.09.002;

submitter keyword: OCTN2, hiPSC-CM, TMT-labelling,Primary carnitine deficiency, LC-MS/MS

Manuel Mayr
contact affiliation	King’s British Heart Foundation Centre of Research Excellence, King's College London, United Kingdom
contact email	manuel.mayr@kcl.ac.uk
lab head
Xiaoke Yin
contact affiliation	Cardiovascular Division, King's College London
contact email	xiaoke.yin@kcl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036026
     1. Label: PRIDE project
     2. Name: Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as novel disease mechanism