Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

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 patho

SUBMITTER: Sara, M Fielder 

PROVIDER: S-SCDT-10_1038-S44321-025-00290-8 | biostudies-other |

REPOSITORIES: biostudies-other