358: CHCHD4 and a Pediatric OXPHOS Collapse

Mantecon M et al., Human Genetics and Genomics Advances - This episode reviews a brief communication reporting a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Functional studies in patient fibroblasts show decreased CHCHD4 protein, marked assembly defects of mitochondrial complexes I and IV, and broad downregulation of electron transport and complex I biogenesis. Lentiviral expression of wild-type CHCHD4 restored OXPHOS proteins and assembly, linking CHCHD4 deficiency to human mitochondrial disease. Key terms: CHCHD4, mitochondrial disease, OXPHOS, complex I, protein import. Study Highlights:A single infant carried a paternal c.5C>T (p.Ser2Phe) CHCHD4 variant and a maternal deletion encompassing CHCHD4, resulting in markedly reduced CHCHD4 protein and severe lactic acidosis with neurological regression. Fibroblast analyses revealed decreased complex I and IV subunits, assembly defects on BN-PAGE, and widespread downregulation of mitochondrial proteins by proteomics, with respiratory electron transport and complex I biogenesis identified as the main dysregulated pathways. Lentiviral overexpression of wild-type CHCHD4 in patient cells restored CHCHD4 levels, rescued complex I and IV protein abundance and assembly, and reversed many proteomic changes, supporting causality. Conclusion:Biallelic CHCHD4 deficiency causes a severe early-onset mitochondrial disease by impairing mitochondrial protein import and assembly of complexes I and IV; restoration of CHCHD4 rescues the molecular defects. Additional cases are needed to define the clinical spectrum and the functional impact of specific variants. Music:Enjoy the music based on this article at the end of the episode. Article title:Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease First author:Mantecon M Journal:Human Genetics and Genomics Advances DOI:10.1016/j.xhgg.2026.100615 Reference:Mantecon M, Chhuon C, Roger K, et al. Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease. Human Genetics and Genomics Advances. 2026;7:100615. doi:10.1016/j.xhgg.2026.100615 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/biallelic-chchd4-oxphos-defect QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-05. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the sections describing CHCHD4 function in the MIA pathway, the pediatric case with biallelic CHCHD4 variants, AlphaFold structural predictions for Ser2Phe, lentiviral complementation rescuing OXPHOS defects, and the proteomics results including selective vulnerability and clinical implications.- transcript topics: MIA pathway and CHCHD4 function in mitochondrial protein import; Genetic case and inheritance pattern (p.Ser2Phe with maternal CHCHD4 deletion); AlphaFold structural prediction of Ser2Phe destabilizing CHCHD4; Functional complementation rescue with WT CHCHD4 in patient fibroblasts; Proteomics results showing OXPHOS defects and selective vulnerability; Clinical implications: CHCHD4 deficiency as a novel cause of mitochondrial disease QC... Chapters (00:00:20) - A cellular blackout: The nuclear power plant(00:02:22) - Mitochondrial dysfunction: The power grid of the cell(00:06:39) - Mitochondrial disease 8, Genetic Errors(00:12:29) - The CRISPR-based diagnosis of iron deficiency(00:18:27) - Bring the light back in mitochondrial disease