PXD064057

PXD064057 is an original dataset announced via ProteomeXchange.

Title	Heart mitochondrial differential solubilisation in CHCD10 (S55L) and control mice
Description	Mutations in CHCHD10, a mitochondrial protein implicated in proteostasis and cristae maintenance, cause autosomal dominant mitochondrial diseases characterized by cardiomyopathy and neurodegeneration. Heterozygous Chchd10 S55L knock-in mice (modeling the human S59L variant) develop progressive mitochondrial cardiomyopathy driven by CHCHD10 aggregation, which is associated with chronic activation of the mitochondrial integrated stress response (mtISR). Here, we demonstrate that cardiac dysfunction is affected by biological sex and is associated with dual defects originating at the onset of disease: (1) early respiratory chain failure linked to cytochrome c depletion and impaired copper homeostasis and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Genetic inactivation of OMA1 delays cardiomyopathy without rescuing CHCHD10 insolubility, proteomic remodeling, cristae defects or OXPHOS impairment, demonstrating that mtISR can be uncoupled from the bioenergetic collapse triggered by CHCHD10 protein aggregation. Proteomic profiling of soluble and insoluble mitochondrial proteins reveals wide-spread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria could be rescued by the exogenous addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Our work reveals that CHCHD10 insolubility and aggregation compromises metabolic resilience by impairing both electron transport and stress adaptation within the IMS, offering new perspectives for the development of therapeutic targets. This repository is connected to PXD064045. The internal idetnfier is: DECTXuxSGj Please note that we had to rename the raw file containing ++ and +- to WT and HET, respectively due to character contstrains in PRIDE submission.
HostingRepository	PRIDE
AnnounceDate	2025-11-07
AnnouncementXML	Submission_2025-11-07_10:32:14.567.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hendrik Nolte
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-19 03:58:36	ID requested
⏵ 1	2025-11-07 10:32:15	announced

Dataset with its publication pending

submitter keyword: Heart, Mus musculus, mitochondria

Thomas Langer
contact affiliation	Max-Planck-Institute for Biology of Ageing Department of Mitochondrial Proteostasis Joseph-Stelzmann-Str. 9b 50931 Cologne
contact email	tlanger@age.mpg.de
lab head
Hendrik Nolte
contact affiliation	Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany
contact email	h.nolte@age.mpg.de
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/2025/11/PXD064057

PRIDE project URI

• PRIDE
  1. PXD064057
     1. Label: PRIDE project
     2. Name: Heart mitochondrial differential solubilisation in CHCD10 (S55L) and control mice