Language
English
Publication Date
10-1-2025
Journal
EMBO Molecular Medicine
DOI
10.1038/s44321-025-00290-8
PMID
40859057
PMCID
PMC12514044
PubMedCentral® Posted Date
8-26-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, Oxidative Phosphorylation, Male, Female, Animals, Mitochondrial Proton-Translocating ATPases, Caenorhabditis elegans, Mutation, Missense, Nervous System Diseases, Child, Mitochondria, Child, Preschool, ATP5F1A, ATP Synthase, Complex V, Mitochondriopathy, Oxidative Phosphorylation, Genetics, Gene Therapy & Genetic Disease; Neuroscience; Organelles
Published Open-Access
yes
Recommended Citation
Fielder, Sara M; Friederich, Marisa W; Hock, Daniella H; et al., "Dominant Negative ATP5F1A Variants Disrupt Oxidative Phosphorylation Causing Neurological Disorders" (2025). Faculty and Staff Publications. 5033.
https://digitalcommons.library.tmc.edu/baylor_docs/5033
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons