PXD031444

PXD031444 is an original dataset announced via ProteomeXchange.

Title	Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy
Description	Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knock-in mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.
HostingRepository	PRIDE
AnnounceDate	2022-03-01
AnnouncementXML	Submission_2022-02-28_23:45:35.658.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nneka Southwell
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-04 15:29:14	ID requested
⏵ 1	2022-02-28 23:45:36	announced

Dataset with its publication pending

submitter keyword: CHCHD10, mitochondria, cardiomyopathy

Giovanni Manfredi
contact affiliation	Brain and Mind Research Institute Weill Cornell Medicine 407 E 61st St, New York, NY, 10065 United States
contact email	gim2004@med.cornell.edu
lab head
Nneka Southwell
contact affiliation	Weill Cornell Medicine
contact email	nns4001@med.cornell.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031444
     1. Label: PRIDE project
     2. Name: Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy