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/

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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-subunits (α:β and α:γ) of the F1 complex.
- In vivo functional studies in C. elegans show these variants are damaging via a dominant negative mechanism; phenotypes are suppressible by extra wild-type copies.
- Proband-derived cells show reduced complex V abundance and activity; ATP5F1A and OSCP-related subunits are decreased.
- Mitochondrial physiology reveals uncoupled oxidative phosphorylation: increased oxygen consumption with decreased membrane potential and ATP.
- Arg207His is a previously reported ATP5F1A variant with neonatal onset and clinical resolution by 18 months, contrasting with the current variants.

QC result: Pass.