Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-08-26
DOI
https://doi.org/10.1038/s44321-025-00290-8
Citations
5
Primary Topic
ATP Synthase and ATPases Research
Type
article
Field-Weighted Citation Impact
4.03

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article

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

Sara M. Fielder, Jacob Lesinski, Kayla Treat, Stephanie A. Morrison et al.
5 citations
EMBO Molecular Medicine
ATP Synthase and ATPases Research
4.03
article

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

Sara M. Fielder, Jacob Lesinski, Kayla Treat, Stephanie A. Morrison, Rocío Rius, Richard Reisdorph, David A. Stroud, Claudia Soler‐Alfonso, Roxanne A. Van Hove, Kim C. Worley, Liana N. Semcesen, Lindsay C. Burrage, Francesco Vetrini, Eric Tycksen, Natasha J. Brown, Cole R. Michel, Tim Schedl, Gary A. Silverman, Stephen C. Pak, Erin Conboy, Jill Anne Rosenfeld, Stephen Matthew Sykes, Farah A. Ladha, Dustin Baldridge, Kevin T. Booth, Hieu D. Hoang, Sarah Govert, Johan L.K. Van Hove, Marisa W. Friederich, Daniella H. Hock, Lisa Emrick, Liana Valin, Tanavi Sharma, Jian Chen, Weimin Yuan, William J. Craigen, Tara E. Samson, Jessie R. Zhang, Sara DaCunha
article en
5 citations

Abstract

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.

EMBO Molecular MedicineVol. 17(10)
Biotechnology Institute (US), Garvan Institute of Medical Research (AU), The University of Melbourne (AU), Baylor College of Medicine (US), Washington University in St. Louis (US), UNSW Sydney (AU), Children's Hospital Colorado (US), Victorian Clinical Genetics Services (AU), Advanced Genomic Technology (United States) (US), Texas Children's Hospital (US), Murdoch Children's Research Institute (AU), Indiana University School of Medicine, Saint Louis University (US), University of Colorado Anschutz Medical Campus (US), Indiana University – Purdue University Indianapolis (US), University of Montana (US), University of Colorado Denver (US)
Armstrong Foundation, Children's Hospital Colorado, Washington University in St. Louis, Children’s Hospital of Wisconsin Research Institute, Children's Hospital Foundation, Murdoch Children's Research Institute, Royal Children's Hospital Foundation, Rare Diseases Clinical Research Network, State Government of Victoria, Mito Foundation, Pierce Armstrong Foundation, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Medical Research Council, National Health and Medical Research Council, National Human Genome Research Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Common Fund
Openalex Percentile: Top 6%
ATP Synthase and ATPases Research
4.03
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