Mitochondrial trifunctional protein (MTP)

The Mitochondrial trifunctional protein (MTP) is a multienzyme complex located in the inner mitochondrial membrane that is essential for the beta-oxidation of long-chain fatty acids (UniProt: P30084). It is a heterooctamer composed of four alpha subunits (HADHA) and four beta subunits (HADHB), which together catalyze three consecutive steps in the fatty acid oxidation spiral: long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase activities (PubMed: 25159725). MTP plays a vital role in energy homeostasis, particularly during periods of fasting or high energy demand, by converting long-chain acyl-CoA esters into acetyl-CoA for the citric acid cycle (StatPearls: NBK559218). Genetic mutations in the subunits of MTP lead to severe metabolic disorders, such as MTP deficiency and LCHAD deficiency, which are characterized by life-threatening hypoglycemia, cardiomyopathy, and liver dysfunction (NIH: GARD). In clinical practice, MTP is a pharmacological target for anti-anginal agents like trimetazidine, which selectively inhibits its thiolase activity to shift cardiac metabolism toward glucose oxidation, enhancing myocardial tolerance to ischemia (DrugBank: DB09069).

Other names

Trifunctional enzymeTFEHADHA/HADHB complexLong-chain 3-hydroxyacyl-CoA dehydrogenase complexMitochondrial trifunctional enzyme

Inhibition of the long-chain 3-ketoacyl-CoA thiolase (LCKAT) component of the MTP complex to shift myocardial metabolism from fatty acid oxidation to glucose oxidation, thereby improving oxygen efficiency in ischemic tissues.