Carnitine mitochondrial permeability

Pastorino, J.G., Snyder, J. W., Serroni, A., Hoek, J. B., and Farber, J. L., 1993, Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition, J. Biol. Chem. 268, pp. 13791-13798... 

The inner mitochondrial membrane is not permeable to long-chain acyl CoA derivatives and so these are transported into the mitochondria as carnitine derivatives by carnitine /acyl carnitine translocase. 

The synthesis of palmitate requires the input of 8 molecules of acetyl CoA, 14 molecules of NADPH, and 7 molecules of ATP. Fatty acids are synthesized in the cytosol, whereas acetyl CoA is formed from pyruvate in mitochondria. Hence, acetyl CoA must be transferred from mitochondria to the cytosol. Mitochondria, however, are not readily permeable to acetyl CoA. Recall that carnitine carries only long-chain fatty acids. The barrier to acetyl CoA is bypassed by citrate, which carries acetyl groups across the inner mitochondrial membrane. Citrate is formed in the mitochondrial matrix by the condensation of acetyl CoA with oxaloacetate (Figyu-e 22.25). When present at high levels, citrate is transported to the cytosol, where it is cleaved hy ATP-citrate lyase. 

Carnitine Carrier The resulting acyl CoA ester is still not permeable to the mitochondrial membrane so a carrier system is needed. In this system the fatty acyl group is transferred from CoA-S to carnitine, diffuses across the membrane, and then transferred back to another CoA-S within the matrix ... 

After transport across the plasma membrane, FAs must be esterified to coenzyme A, on the outer mitochodrial membrane by long chain acyl-CoA synthetase activity (ACSL C12 to C20) before they can undergo oxidative degradation. This reaction is coupled with two ATP hydrolysis to AMP and 2Pi. The mitochondrial membrane is not permeable to long chain acyl-CoA (i.e., C16-C18), therefore requires the initial conversion of acyl-CoA to an ester acylcamitine, followed by transport of the acylcamitine across the inner mitochondrial membrane into the mitochondrial matrix and subsequent delivery of acyl-CoA [126], This process is referred to as carnitine shuttle and requires the concerted action of 3 proteins 6 ... 

The second site may include two possibilities one is on the carnitine acyl transferase system and the other involves formation of palmitoyl-S-pantetheine and its non-enzymatic transport through the mitochondrial membranes followed by oxidation in -oxidation system after conversion to palmitoyl CoA. The former possibility may be supported by the difference in effectiveness of pantethine between the palmitate and octanoate oxidation reactions ( Fig.3, 4 and 6 ) and between the ketogenic reactions from these two substrates ( Fig.7 ), because octanoic acid is freely permeable through the mitochondrial membranes. The latter possibility was based on the findings on the formation of acyl pantetheine in rat liver micro-somes [ 10 ] and on the enzymatic interconversion between acyl CoA and acyl pantetheine [ 14 ] and on the much lower susceptibility of acyl pantetheine to3-oxidation than acyl CoA [ 14 ]. But this has been ruled out by the finding that palmitoyl-S-pantetheine did not serve as the substrate of the ketogenic reaction ( fig.7 ). 

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