123: Dominant-negative ATP5F1A variants and uncoupled oxidative phosphorylation

Fielder SM et al et al., EMBO Molecular Medicine - This episode examines a study that identifies de novo heterozygous missense variants in ATP5F1A that cause developmental and movement disorders by destabilizing mitochondrial complex V. Functional C. elegans modeling and patient-cell assays reveal a dominant negative mechanism and uncoupled oxidative phosphorylation. Key terms: ATP5F1A, complex V, oxidative phosphorylation, dominant negative, mitochondrial disease. Study Highlights:Six probands carry four de novo heterozygous ATP5F1A missense variants located at α:β or α:γ contact points of the F1 ATP synthase. CRISPR knock-ins in C. elegans show the variants are damaging and act dominantly, with phenotypes suppressed by extra wild-type copies. Patient fibroblasts and lymphoblastoid cells display reduced complex V abundance and activity, and proband fibroblasts show increased oxygen consumption but decreased membrane potential and ATP consistent with uncoupling. Proteomics, BN-PAGE, and biochemical assays support destabilization of complex V as the pathophysiologic mechanism. Conclusion:De novo heterozygous ATP5F1A missense variants can act as dominant negative alleles that reduce complex V stability and activity and cause uncoupled oxidative phosphorylation, producing a spectrum of persistent neurological phenotypes; integrated functional studies are required to classify such variants. Music:Enjoy the music based on this article at the end of the episode. Article title:Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders First author:Fielder SM et al Journal:EMBO Molecular Medicine DOI:10.1038/s44321-025-00290-8 Reference:Fielder SM et al., Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders. EMBO Mol Med (2025). DOI:10.1038/s44321-025-00290-8 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/dominantnegative-atp5f1a-variants-uncouple-complex-v-and-drive-neurological-disease QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-31. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's coverage of structure, variants, and function of ATP5F1A; dominant negative mechanism; C. elegans modeling; patient-cell metabolism; comparison to Arg207His; clinical implications.- transcript topics: ATP synthase structure and Complex V; ATP5F1A dominant negative variants; Variant localization at α:β and α:γ interfaces; C. elegans functional modeling and rescue; Proteomics and BN-PAGE analyses of patient cells; Mitochondrial respiration and uncoupled oxidative phosphorylation QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Six probands with heterozygous de novo ATP5F1A variants presented with developmental delay, intellectual disability, and movement disorders.- Variants map to contact points between the α-subunit and β- or γ... Chapters (00:00:00) - Genetics of mitochondrial dysfunction in children(00:06:38) - The mitochondrial DNA defects of the PR207(00:11:22) - Mitochondrial diseases 7, Uncoupling(00:15:34) - What do you think are the biggest hurdles to using this kind of(00:16:39) - Mitochondrial ATP synthase dysregulation