HADHA

HADHA encodes the alpha subunit of the mitochondrial trifunctional protein (MTP/TFP), a heterotetrameric complex (alpha2-beta2) with HADHB that is bound to the matrix face of the mitochondrial inner membrane and catalyzes the last three steps of long-chain fatty acid beta-oxidation. The alpha subunit carries TWO of these activities: long-chain enoyl-CoA hydratase (LCEH, EC 4.2.1.17), which hydrates 2-trans-enoyl-CoA to (3S)-3-hydroxyacyl-CoA, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD, EC 1.1.1.211), which oxidizes (3S)-3-hydroxyacyl-CoA to 3-oxoacyl-CoA using NAD+. The third step (thiolytic cleavage to acetyl-CoA) is carried by the beta subunit (HADHB). The enzyme is specific for long-chain (C10-C16) acyl-CoA substrates, including saturated and unsaturated species. Independently of the beta subunit, the alpha subunit also exhibits a monolysocardiolipin acyltransferase activity that participates in cardiolipin remodeling. Deficiency of HADHA causes isolated LCHAD deficiency and generalized mitochondrial trifunctional protein deficiency, presenting with hypoketotic hypoglycemia, cardiomyopathy, peripheral neuropathy and pigmentary retinopathy, and associated with maternal HELLP syndrome / acute fatty liver of pregnancy.

Disorders

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