Trifunctional enzyme subunit alpha, mitochondrial

HADHA (Trifunctional enzyme subunit alpha, mitochondrial) is a 763-amino acid mitochondrial protein that catalyzes the final three reactions of long-chain fatty acid beta-oxidation, converting fatty acids to acetyl-CoA for energy production (UniProt: P40939). The protein functions as part of a heterotetrameric complex with HADHB, and independently exhibits cardiolipin acyltransferase activity involved in remodeling of this critical mitochondrial membrane phospholipid.

Mutations in HADHA cause autosomal recessive mitochondrial trifunctional protein deficiency (MTPD1, MIM 609015) and long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency, MIM 609016), characterized by severe metabolic dysfunction affecting fatty acid oxidation with phenotypes ranging from early-onset cardiomyopathy to adult-onset myopathy and neuropathy (UniProt: P40939). HADHA is also implicated in maternal acute fatty liver of pregnancy when affecting fetal genotypes.

HADHA shows increased abundance in post-mortem Alzheimer's disease brain tissue relative to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of 0.37 across three fractions in TMT-labeled proteomic analysis. This modest upregulation may reflect altered mitochondrial bioenergetics or lipid metabolism in the AD brain environment.