HADHA

Function

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

Involvement in disease

Mitochondrial trifunctional protein deficiency 1

MTPD1

An autosomal recessive metabolic disorder of long-chain fatty acid oxidation, biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. The disease phenotype ranges from a fatal form characterized by early-onset cardiomyopathy, cardiac failure and early death to less severe, late-onset forms with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy as key features.

None

The disease is caused by variants affecting the gene represented in this entry.

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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).

None

The disease is caused by variants affecting the gene represented in this entry.

Pathway

Lipid metabolism; fatty acid beta-oxidation.

Sequence Similarities

In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.

In the central section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.

Cellular localization

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

Alternative names

HADH, HADHA, 78 kDa gastrin-binding protein, Monolysocardiolipin acyltransferase, TP-alpha

Database links

swissprot:P40939 entrezGene:3032 entrezGene:3030 swissprot:P55084 omim:600890 omim:143450