Carnitine shuttle (mitochondrial import of long-chain fatty acids)

The carnitine shuttle is the system that imports long-chain fatty acids into the mitochondrial matrix for beta-oxidation. Long-chain acyl-CoA cannot cross the inner mitochondrial membrane, so it is transiently converted to acylcarnitine, transported across the membrane, and converted back to acyl-CoA inside the matrix. First, the plasma-membrane sodium-dependent carnitine transporter SLC22A5 (OCTN2) imports L-carnitine into the cell (and mediates its renal reabsorption), supplying the carnitine pool. Carnitine palmitoyltransferase 1 (CPT1; the liver isoform is CPT1A), on the mitochondrial OUTER membrane, catalyses the committed, rate-limiting, malonyl-CoA-inhibited step: transfer of a long-chain acyl group from acyl-CoA to carnitine, giving long-chain acylcarnitine + CoA. The carnitine/acylcarnitine translocase SLC25A20 (CACT), an SLC25 carrier of the INNER membrane, then antiports acylcarnitine into the matrix in exchange for free carnitine. Finally carnitine palmitoyltransferase 2 (CPT2), on the matrix face of the inner membrane, reverses the CPT1 reaction — regenerating long-chain acyl-CoA (and releasing carnitine, which CACT recycles back out) so that beta-oxidation can proceed. Inherited defects of each component cause fatty-acid-oxidation disorders that typically present with hypoketotic hypoglycemia, cardiomyopathy/arrhythmia and/or myopathy: SLC22A5 → primary (systemic) carnitine deficiency; CPT1A → CPT1A deficiency; SLC25A20 → carnitine- acylcarnitine translocase deficiency; CPT2 → CPT2 deficiency (the myopathic form is a common cause of exercise-induced rhabdomyolysis).