2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial

BCKDHA (2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial) is the alpha subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex, a key mitochondrial enzyme that catalyzes oxidative decarboxylation of branched-chain amino acids (valine, leucine, isoleucine) to generate energy-yielding acyl-CoA products (UniProt: P12694). The protein functions as part of a heterotetrameric E1 subunit, performing the initial decarboxylation step in branched-chain amino acid catabolism.

BCKDHA is primarily expressed in mitochondria across metabolically active tissues. Pathogenic mutations cause maple syrup urine disease (MSUD1A), an autosomal recessive metabolic disorder characterized by branched-chain amino acid accumulation, encephalopathy, and neurodegeneration (UniProt: P12694). The severe neurological manifestations reflect critical dependence of the nervous system on proper branched-chain amino acid metabolism.

In Alzheimer's disease, BCKDHA is significantly upregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of +0.41 across analyzed subcellular fractions (Chaparral AD proteomics). This upregulation may reflect compensatory metabolic responses or altered energy metabolism in AD pathology, though functional implications remain to be determined.