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. Functional evaluation in C. elegans revealed that all variants tested were damaging to gene function via a dominant negative genetic mechanism. Biochemical and proteomics studies showed a marked reduction in complex V abundance and activity in proband-derived blood cells and fibroblasts. Mitochondrial physiology studies in fibroblasts revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylat

SUBMITTER: Fielder SM 

PROVIDER: S-EPMC12265762 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature