Amphiphilic interactions of long-chain fatty acylcarnitines with membranes: potential involvement in ischemic injury

Abstract

Under physiological conditions, the heart preferentially utilizes fatty acids to meet its energy requirements. Non-esterified free fatty acids (NEFA) in plasma are bound to albumin with only small quantities free in solution, in equilibrium with the albumin-bound NEFA [1]. A significant portion of NEFA utilized by the cardiomyocyte originates from hydrolysis by endothelial surface-bound lipoprotein lipase of triacylglycerols of the circulating lipoproteins [2]. Unbound NEFA transverses the sarcolemma (SL) either passively or facilitated by specific membrane proteins such as SL fatty acid binding protein [3]. Like plasma NEFA, cytosolic unbound NEFA exist in equilibrium with a larger quantity of intracellular NEFA bound to fatty acid binding protein [3]. Metabolism of cytosolic NEFA proceeds initially by thioesterification into fatty acyl-CoA esters catalyzed by acyl-CoA synthetase that is localized predominantly on the outer mitochondrial membrane (Figure 1, normoxia). Due to the limited availability of CoA, most of which is contained in the mitochondrial matrix, the fatty acyl-CoA synthetase activity is substrate dependent. Long chain fatty acyl-CoA cannot pass the inner mitochondrial membrane to become degraded by the β-oxidation. The cytosolic and matrix pools of CoA are also strictly separated and the cytosolic long chain fatty acyl-CoA is first converted to long chain fatty acylcarnitine (LCAC) by carnitine fatty acyltransferase I, localized at the inner surface of the mitochondrial outer membrane [4]. LCAC thus generated is translocated across the mitochondrial inner membrane via the specific acylcarnitine-carni-tine antiporter (translocase) [5]. Inside the mitochondrial matrix the LCAC is transesterified to yield free carnitine and fatty acyl-CoA by carnitine acyltransferase II localized at the inner surface of the mitochondrial inner membrane [3]. Total carnitine content (free and esterified) on each side of the inner mitochondrial membrane remains relatively constant. Complete β-oxidation of fatty acyl-CoA results in the production of acetyl-CoA fragments with concomitant reduction of NAD⁺ and FAD. Acetyl-CoA enters the citric acid cycle with production of additional NADH and FADH₂. The reducing equivalents formed yield ATP in the mitochondrial electron transport chain tightly coupled to the ATP synthetase.

“Altogether, definitive evidence for long chain fatty acylcarnitine as a mediator of impaired contractile function is still lacking, but experimental evidence for arrhythmogenicity of accumulated acylcarnitine seems rather convincing.”