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Lookup NU author(s): Professor Robert TaylorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 .Mitochondrial disorders show remarkable clinical and genetic heterogeneity and result from variants in either mitochondrion- or nucleus-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects. Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4 . CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. 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 cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.
Author(s): Mantecon M, Chhuon C, Roger K, Guerrera IC, Bole C, Nitschke P, Dufeu-Berat C-M, Ashcroft M, Taylor RW, Boddaert N, Rotig A
Publication type: Article
Publication status: Published
Journal: Human Genetics and Genomics Advances
Year: 2026
Volume: 7
Issue: 3
Print publication date: 09/07/2026
Online publication date: 14/04/2026
Acceptance date: 10/04/2026
Date deposited: 12/05/2026
ISSN (electronic): 2666-2477
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.xhgg.2026.100615
DOI: 10.1016/j.xhgg.2026.100615
Data Access Statement: The genome sequencing data supporting the current study have not been deposited in a public repository because consent was not obtained for this. The published article includes all other data generated or analyzed during this study, or it is readily available from the authors.
PubMed id: 41981912
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