HADHA

This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]

Full Name

Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Alpha

Function

Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:8135828, PubMed:1550553, PubMed:29915090, PubMed:30850536).

The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090).

Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (PubMed:30850536).

Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA described here carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities while the trifunctional enzyme subunit beta/HADHB bears the 3-ketoacyl-CoA thiolase activity (PubMed:8135828, PubMed:29915090, PubMed:30850536).

Independently of the subunit beta, the trifunctional enzyme subunit alpha/HADHA also has a monolysocardiolipin acyltransferase activity (PubMed:23152787).

It acylates monolysocardiolipin into cardiolipin, a major mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes in the generation of ATP (PubMed:23152787).

Allows the acylation of monolysocardiolipin with different acyl-CoA substrates including oleoyl-CoA for which it displays the highest activity (PubMed:23152787).

Biological Process

Cardiolipin acyl-chain remodeling Source: UniProtKB
Fatty acid beta-oxidation Source: ComplexPortal
Response to insulin Source: Ensembl
Response to xenobiotic stimulus Source: Ensembl

Cellular Location

Mitochondrion; Mitochondrion inner membrane. Protein stability and association with mitochondrion inner membrane do not require HADHB.

Involvement in disease

Mitochondrial trifunctional protein deficiency (MTPD):
A disease biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. Variable clinical manifestations include hypoglycemia, cardiomyopathy, delayed psychomotor development, sensorimotor axonopathy, generalized weakness, hepatic dysfunction, respiratory failure. Sudden infant death may occur. Most patients die from heart failure.
Long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency):
The clinical features are very similar to TFP deficiency. Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the TFP complex are normal or only slightly reduced.
Maternal acute fatty liver of pregnancy (AFLP):
Severe maternal illness occurring during pregnancies with affected fetuses. This disease is associated with LCHAD deficiency and characterized by sudden unexplained infant death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome).