Hydroxyacyl-CoA dehydrogenase trifunctional effector protein subunit alpha (HADHA) (HADHA)

Hydroxyacyl-CoA dehydrogenase trifunctional effector protein subunit alpha (HADHA) is a key component of the mitochondrial trifunctional protein (MTP), a multienzyme complex located in the inner mitochondrial membrane that is vital for the beta-oxidation of long-chain fatty acids [1, 2]. The HADHA subunit specifically provides two of the three enzymatic activities of the complex: long-chain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase [1]. This protein is essential for maintaining energy homeostasis, particularly in tissues with high energy demands like the heart, liver, and skeletal muscle, by converting long-chain fatty acids into acetyl-CoA [2, 4]. Deficiencies in HADHA are associated with severe metabolic conditions, including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and mitochondrial trifunctional protein deficiency, which can manifest as life-threatening hypoglycemia, cardiomyopathy, and skeletal myopathy [4]. Additionally, maternal carriers of HADHA mutations are at increased risk for developing acute fatty liver of pregnancy (AFLP) and HELLP syndrome if the fetus is affected [1, 4]. While primarily studied in the context of genetic disorders, HADHA is a target for pharmacological intervention using PPAR-alpha agonists like bezafibrate, which can induce the expression of the enzyme to boost residual activity in patients with partial deficiencies [3].

Other names

Trifunctional enzyme subunit alpha, mitochondrialLong-chain enoyl-CoA hydrataseLong-chain 3-hydroxyacyl-CoA dehydrogenaseLCHADTP-alpha78 kDa gastrin-binding protein

PPAR-alpha agonist-mediated transcriptional upregulation of HADHA to enhance long-chain fatty acid beta-oxidation