PXD069027

PXD069027 is an original dataset announced via ProteomeXchange.

Title	Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease
Description	Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from genetic variants in either mitochondrial-encoded or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly (MIA) pathway that imports small cysteine-containing substrates such as TIM proteins, complex I and IV subunits and/or assembly factors. We report a child subject with biallelic CHCHD4 variants who presented with severe lactic acidosis, psychomotor and neurological regression. Western blot analysis in subject-derived fibroblasts showed decreased steady-state levels of CHCHD4 and a severe oxidative phosphorylation (OXPHOS) defect. Moreover, diminished assembly of both complexes I and IV was also observed. To demonstrate that the segregating CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring steady-state levels of complex I and IV proteins and the associated OXPHOS assembly defects. Proteomic studies and Reactome enrichment of the altered proteins pointed to respiratory electron transport and complex I biogenesis as the main dysregulated pathways. More detailed analyses revealed a severe loss of several complex I and IV subunit proteins and/or assembly factors, that were rescued by overexpression of wild-type CHCHD4. CHCHD4 is involved in the import of several other mitochondrial proteins, has numerous targets and interacting factors and has been shown to be involved in the export of iron-sulfur clusters synthesized inside mitochondria, suggesting involvement in several mitochondrial and non-mitochondrial functions. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a new cause of dysregulated mitochondrial protein import, and suggests this gene should be investigated in subjects with this rare form of mitochondrial disease.
HostingRepository	PRIDE
AnnounceDate	2026-01-21
AnnouncementXML	Submission_2026-01-21_09:33:07.844.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chiara guerrera
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-01 01:48:48	ID requested
⏵ 1	2026-01-21 09:33:08	announced

Dataset with its publication pending

submitter keyword: CHCHD4, timsTOF HT, evosep, mitochondrial disorders

Ida Chiara Guerrera
contact affiliation	Necker Proteomics, Université Paris Cité - Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR3633, Paris 75015, France.
contact email	chiara.guerrera@inserm.fr
lab head
Chiara guerrera
contact affiliation	Necker proteomics, INSERM
contact email	chiara.guerrera@inserm.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069027
     1. Label: PRIDE project
     2. Name: Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease