ATP5F1A

ATP5F1A is the gene that encodes the alpha subunit of the mitochondrial ATP synthase complex, specifically the F1 catalytic sector. In humans, ATP5F1A is encoded in the nucleus, transcribed and translated into a protein that is imported into mitochondria where it becomes part of the F1 portion of the enzyme.

Functionally, the F1 sector forms a hexamer composed of three alpha and three beta subunits arranged alternately. The alpha subunit contributes to the structural framework and nucleotide binding but is not the primary catalytic subunit; the catalytic activity resides mainly in the beta subunits. The F1 complex, together with the F0 sector embedded in the inner mitochondrial membrane, converts the energy of the proton motive force into ATP from ADP and inorganic phosphate. The alpha subunit interacts with other F1 subunits during catalysis and assembly, helping to coordinate conformational changes that drive ATP synthesis.

Localization and assembly involve import of the nucleus-encoded protein into mitochondria, followed by incorporation into the soluble F1 complex in the mitochondrial matrix and subsequent association with the F0 sector to form the holoenzyme. Expression of ATP5F1A is widespread, reflecting the universal role of ATP synthase in cellular energy production.

Clinical significance of ATP5F1A variants is limited but includes reports of mitochondrial disease associated with complex V deficiencies. Such phenotypes can be heterogeneous, ranging from early-onset lactic acidosis and encephalopathy to later-onset myopathy, and typically require genetic and biochemical confirmation.