Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial

HADH (hydroxyacyl-coenzyme A dehydrogenase, mitochondrial) is a 34 kDa enzyme that catalyzes the third step of mitochondrial fatty acid beta-oxidation, processing medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10) (UniProt: Q16836). The protein also participates in regulating insulin secretion through inhibition of glutamate dehydrogenase 1 and maintains normal spermatogenesis by reducing fatty acid accumulation in testicular tissue.

HADH localizes to mitochondria and is involved in cellular energy metabolism. Genetic defects in HADH cause autosomal recessive metabolic disorders including 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (MIM 231530) and familial hyperinsulinemic hypoglycemia type 4 (MIM 609975), both characterized by metabolic dysregulation and neurological complications such as seizures and mental retardation (UniProt: Q16836).

In Alzheimer's disease, HADH is significantly upregulated in post-mortem human brain tissue compared to age-matched controls, with a mean log2 fold-change of +0.545 (Chaparral AD proteomics, TMT-labeled DDA proteomics across subcellular fractions). This elevation suggests involvement of lipid metabolism dysfunction in AD pathology.