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 path

SUBMITTER: Fielder SM 

PROVIDER: S-EPMC12514044 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature