Physiological Importance Of The Mitochondrial Carnitine Palmitoyltransferase I

2.1. Role in Mitochondrial Fatty Acid ß-Oxidation

Mammalian mitochondrial ß-oxidation of fatty acids, the process by which fatty acids are oxidized,2 provides the primary source of energy for the heart and skeletal muscle. In liver, when blood glucose levels are low, the capacity for fatty acid ß-oxidation

* Corresponding author: C. PRIP-BUUS, Endocrinologie, Métabolisme et Développement, 9 rue J. Hetzel, F-92190 Meudon, Tel: 33 1 45 07 51 68, Fax: 33 1 45 07 50 39, Email: [email protected]

Current Views of Fatty Acid Oxidation and Ketogenesis: From Organelles to Point Mutations edited by Quant and Eaton, Kluwer Academic / Plenum Publishers, New York, 1999. 1

increases allowing the production of ketone bodies (acetoacetate and (i-hydroxybutyrate), which serve as alternative fuels of respiration in nonhepatic tissues. Cytosolic long-chain fatty acids (LCFA) are first activated by long-chain acyl-CoA synthase on the outer mitochondrial membrane (OMM). The long-chain acyl-CoAs (LC-CoA) are substrates for the CPT system which allows them to overcome the impermeability of the inner mitochondrial membrane (IMM) and thus to be transported into the mitochondrial matrix, where the P-oxidation of LC-CoAs takes place. The CPT system requires the sequential action of CPT I (anchored at the OMM), the carnitine-acylcarnitine translocase (an integral protein of the IMM) and CPT II (located at the inner face of the IMM). In this system, CPT I catalyses the rate-limiting step of fatty acid oxidation.1 A unique feature of CPT I is its potent inhibition by malonyl-CoA, the first intermediate of fatty acid biosynthesis.5 This dual role of malonyl-CoA as intermediate and inhibitor provides not only a mechanism for physiological regulation of |i-oxidation in liver and other tissues but also a coordinated control of fatty acid synthesis, esterification and oxidation.

By contrast to CPT II which has been found as one isoform, mammalian tissues express two isoforms of CPT I, the liver (L-CPT I) and the muscle (M-CPT I) forms, that are approximately 62% identical in amino acid sequence.6-10 The liver isoform is present in the mitochondria of liver, pancreas, kidney, brain and most other tissues, while M-CPT I is the isoform expressed in skeletal muscle as well as in white and brown adipocytes.3 L-CPT I is highly expressed in the fetal heart, but its expression decreases after birth with a concomitant increase in the expression of the M-CPT I.3,4 Unlike L-CPT I which displays altered sensitivity to malonyl-CoA under different physiopatho-logical conditions,11-16 M-CPT I is very sensitive to malonyl-CoA inhibition but does not undergo any alteration of its sensitivity to malonyl-CoA.3 The concentration of malonyl-CoA is much lower in heart than in rat liver,1 but it is sufficient to inhibit fatty acid oxidation. The important question in cardiac metabolism, which is still unsolved, is how can fatty acid oxidation proceed in the presence of malonyl-CoA?

LCFA oxidation occurs mainly in mitochondria but rat liver microsomes and peroxisomes contain also both membrane-bound/malonyl-CoA-sensitive and soluble/ malonyl-CoA-insensitive (luminal) CPT-like enzymes.17-19 Thus, a similar fatty acid transport system operates in mitochondria, peroxisomes and microsomes, but it seems that the components involved in these systems are all different.20 The physiological role of these fatty acid transport systems in microsomes and peroxisomes remains unclear. The microsomal CPTs may have a role in providing fatty acids for transport of proteins through the Golgi apparatus and for acylation of secreted proteins. Since oxidation of very long-chain fatty acids is confined to peroxisomes, a possible role for the peroxisomal CPTs may be to shuttle chain-shorted products out of peroxisomes for further oxidation in mitochondria.

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