Lipid Biochemistry

Role of carnitine in fatty acid oxidation

Since the inner mitochondrial membrane is impermeable to acyl-CoA moieties, a specific transporter is required. Acyl-CoA moieties are transported from the cytosol into the mitochondrial matrix by carnitine (ß hydroxy-γ-trimethylammonium butyrate), and the transport process is called the carnitine shuttle (see figure 4.3).

The process of transport can be summarized as follows: Acyl-CoA penetrates the outer membrane of mitochondria through pores. It reacts with carnitine to yield the acyl-carnitine derivative in a reaction catalyzed by carnitine-palmitoyltransferase I (CPT I). Malonyl-CoA inhibits this enzyme (which is the major control point) thus preventing entry of fatty acids into the mitochondrial matrix. In this way, when fatty acid synthesis is in progress, malonyl-CoA prevents fatty acids catabolism. The acyl-carnitine is shuttled across the inner mitochondrial membrane by the carnitine-acyl-carnitine translocase (CACT), which acts as a membrane carnitine acylcarnitine exchange transporter. Once inside the mitochondrial matrix acyl-carnitine is converted back to its acyl-CoA derivative, the substrate for ß-oxidation. This reaction is catalyzed by carnitine-palmitoyltransferase II (CPT II), which is attached to the inside of the inner mitochondrial membrane.

Carnitine deficiency

Carnitine deficiency results in impaired energy production from long chain fatty acids, particularly during periods of fasting or stress. Primary carnitine deficiency is an autosomal recessive disorder that affects mitochondrial ß-oxidation and is due to the lack of the organic cationic/carnitine transporter 2. It is characterized by hypoglycemia, muscular weakness, cardiomyopathy and liver dysfunction. Secondary carnitine deficiency results from defects in fatty acids oxidation, such as medium chain acyl-CoA dehydrogenase deficiency and is characterized by myopathy and hepatomegaly. It may also accompany alcohol cirrhosis and renal failure and chronic hemodialysis.

Carnitine palmitoyltransferase (CPT) deficiency

There are two CPT enzymes, CPT-1 (in outer mitochondrial membrane) and CPT-2 (in inner mitochondrial membrane) and three isoforms of CPT-1 which are encoded by different genes: liver-type (CPT-1A), muscle-type (CPT-1B) and brain-type (CPT1C). Only deficiency of the liver type, CPT-1A has been reported in humans.

CPT-1A deficiency is usually triggered by fasting or viral infection, and is characterized by nonketogenic hypoglycemia, mild hyperammonemia, elevated plasma free fatty acids and abnormal liver function tests. In children it results in altered mental ability/stature and hepatomegaly.

CPT-2 deficiency is more common in adults but can occur in infancy and neonatal period, with predominant muscular involvement. The neonatal form is characterized by respiratory distress, seizures, altered mental ability/stature, hepatomegaly, cardiomegaly and cardiac arrhythmia.