A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation

Abstract

Over the years, the mitochondrial fatty acid β-oxidation (FAO) pathway has been characterised at the biochemical level as well as the molecular biological level. FAO plays a pivotal role in energy homoeostasis, but it competes with glucose as the primary oxidative substrate. The mechanisms behind this so-called glucose-fatty acid cycle operate at the hormonal, transcriptional and biochemical levels. Inherited defects for most of the FAO enzymes have been identified and characterised and are currently included in neonatal screening programmes. Symptoms range from hypoketotic hypoglycaemia to skeletal and cardiac myopathies. The pathophysiology of these diseases is still not completely understood, hampering optimal treatment. Studies of patients and mouse models will contribute to our understanding of the pathogenesis and will ultimately lead to better treatment.

Fig. 1

Mitochondrial fatty acid β-oxidation in humans a and in the mouse b. After transport across the plasma membrane, fatty acids are activated to acyl-CoAs at the cytosolic site. CPT1 converts the acyl-CoA into an acylcarnitine, which is subsequently transported across the mitochondrial membrane by CACT. CPT2 converts the acylcarnitine back into an acyl-CoA. Long chain acyl-CoAs are metabolised by the membrane bound enzymes, very long chain acyl-CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (MTP), which has hydratase, long chain hydroxyacyl-CoA dehydrogenase (LCHAD) and thiolase activity. Short and medium chain acyl-CoAs are metabolised in the mitochondrial matrix by medium chain acyl-CoA dehydrogenase (MCAD), short chain acyl-CoA dehydrogenase (SCAD), crotonase, medium and short chain hydroxyacyl-CoA dehydrogenase (M/SCHAD) and medium chain 3-ketoacyl-CoA thiolase (MCKAT). The oxidation of unsaturated fatty acids such as oleic acid requires the action of an isomerase [dodecenoyl-CoA delta isomerase (DCI)]. C18 denotes an acyl-CoA with a chain length of 18 carbon atoms, and so forth