Carnitine palmitoyltransferase 2 and carnitine/acylcarnitine translocase are involved in the mitochondrial synthesis and export of acylcarnitines.
Acylcarnitines are commonly used in the diagnosis of mitochondrial fatty acid β-oxidation disorders (mFAODs). It is generally assumed that this plasma acylcarnitine profile reflects the mitochondrial accumulation of acyl-CoAs. The identity of the enzymes and the mitochondrial and plasmalemmal transporters involved in the synthesis and export of these metabolites have remained undefined. We used lentiviral shRNA to knock down the expression of medium-chain acyl-CoA dehydrogenase (MCAD) in control and carnitine palmitoyltransferase 2 (CPT2)-, carnitine/acylcarnitine translocase (CACT)-, and plasmalemmal carnitine transporter (OCTN2)-deficient human fibroblasts. These cell lines, including mock-transduced controls, were loaded with decanoic acid and carnitine, followed by the measurement of the acylcarnitine profile in the extracellular medium. In control fibroblasts, MCAD knockdown markedly increased the production of octanoylcarnitine (3-fold, P<0.01). OCTN2-deficient cell lines also showed extracellular accumulation of octanoylcarnitine (2.8-fold, P<0.01), suggesting that the cellular export of acylcarnitines does not depend on OCTN2. In contrast, in CPT2- and CACT-deficient cells, the accumulation of octanoylcarnitine in the medium did not significantly increase in the MCAD knockdown. Similar results were obtained using pharmacological inhibition of CPT2 in fibroblasts from MCAD-deficient individuals. This shows that CPT2 and CACT are crucial for mitochondrial acylcarnitine formation and export to the extracellular fluids in mFAOD.-Violante, S., IJlst, L., te Brinke, H., Tavares de Almeida, I., Wanders, R. J. A., Ventura, F. V., Houten, S. M. Carnitine palmitoyltransferase 2 and carnitine/acylcarnitine translocase are involved in the mitochondrial synthesis and export of acylcarnitines.
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acylcarnitines acyl-CoAs acyl-CoA carnitine carnitine acylcarnitine carnitine fatty acid decanoic acid carnitine Acylcarnitines acylcarnitine octanoylcarnitine Carnitine acylcarnitines carnitine acylcarnitine OCTN2 CPT2 CACT MCAD octanoylcarnitine CPT2 MCAD CPT2 CACT Carnitine palmitoyltransferase 2 carnitine/acylcarnitine translocase medium-chain acyl-CoA dehydrogenase MCAD carnitine palmitoyltransferase 2 CPT2 acylcarnitines carnitine/acylcarnitine translocase CACT carnitine transporter OCTN2 MCAD OCTN2 Carnitine palmitoyltransferase 2 carnitine/acylcarnitine translocase octanoylcarnitine acylcarnitine acylcarnitine Carnitine carnitine acylcarnitine