123: Dominant‑Negative ATP5F1A Variants Uncouple Complex V and Drive Neurological Disease

️ Episode 123: Dominant‑Negative ATP5F1A Variants Uncouple Complex V and Drive Neurological Disease In this episode of PaperCast Base by Base, we explore how de novo heterozygous ATP5F1A missense variants disrupt mitochondrial ATP synthase and manifest as pediatric neurological disorders, revealing a dominant‑negative mechanism and an isolated Complex V defect. Study Highlights:The authors describe six probands with developmental delay, dystonia, pyramidal tract signs and failure to thrive, each carrying ATP5F1A variants clustered at the α–β or α–γ interfaces of the F1 sector of ATP synthase. In vivo CRISPR knock‑ins of orthologous variants in C. elegans behaved dominantly, slowed development and locomotion, and activated a mitochondrial stress response that was dose‑dependently suppressed by adding wild‑type gene copies. Patient‑derived cells showed reduced abundance and ATPase activity of Complex V, with increased oxygen consumption but decreased mitochondrial membrane potential and ATP levels, indicating uncoupled oxidative phosphorylation. Structural modeling supported disrupted subunit interactions, and proteomics demonstrated an isolated Complex V deficiency distinct from earlier reports for other ATP5F1A alterations. Conclusion:This work expands the genetic and phenotypic spectrum of ATP5F1A‑related disease and establishes ATP5F1A as a leading nuclear cause of Complex V deficiency while highlighting organismal modeling as a powerful approach to resolve variants of uncertain significance. Reference:Fielder SM, Friederich MW, Hock DH, Zhang JR, Valin LM, Rosenfeld JA, Booth KTA, Brown NJ, Rius R, Sharma T, Semcesen LN, Worley KC, Burrage LC, Treat K, Samson T, Govert S, DaCunha S, Yuan W, Chen J, Lesinski J, Hoang H, Morrison SA, Ladha FA, Van Hove R, Michel CR, Reisdorph R, Tycksen E, Baldridge D, Silverman GA, Soler‑Alfonso C, Conboy E, Vetrini F, Emrick L, Craigen WJ, Undiagnosed Diseases Network, Sykes SM, Stroud DA, Van Hove JLK, Schedl T, Pak SC. Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders. EMBO Molecular Medicine. 2025.  https://doi.org/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:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/   On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Keywords: ATP5F1A; Complex V; dominant negative; mitochondrial uncoupling; neurological disorders 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

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