Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Chiara guerrera  

LAB HEAD: Ida Chiara Guerrera

PROVIDER: PXD069027 | Pride | 2026-01-21

REPOSITORIES: Pride