Metabolism: The carnitine shuttle and fatty acid metabolism

Whereas short-chain and medium-chain fatty acids can diffuse directly across the mitochondrial membranes, the transport long-chain fatty acids requires the activity of carnitine palmitoyltransferase (CPT) enzymes. CPT I, located on the outer mitochondrial membrane, catalyzes the transfer of the fatty acyl group from fatty acyl-CoA to carnitine, forming fatty acylcarnitine. Fatty acylcarnitine is then able to pass through the mitochondrial inner membrane using a transport protein called the carnitine-acylcarnitine translocase (CACT or CACT1). Once inside the mitochondrial matrix, fatty acylcarnitine is converted back into fatty acyl-CoA by another enzyme called CPT II, which is located on the inner mitochondrial membrane. Now in the form of fatty acyl-CoA, the fatty acids can undergo beta-oxidation within the mitochondria.

Figure 1 Carnitine shuttle

CPT II deficiency has an autosomal recessive inheritance pattern. Individuals with CPT II deficiency experience hypoglycemia and muscle weakness, particularly during times of increased energy demand. In some patients, accumulated fatty acid derivatives leads to mitochondrial dysfunction, muscle damage, and rhabdomyolysis, a condition characterized by the breakdown of muscle tissue and the release of toxic substances into the bloodstream. Managing CPT II deficiency often involves dietary modifications and strategies to these complications.