Carnitine acylcarnitine translocase in ischemia

Abstract

The role of fatty acid oxidation as a major source of energy to the contractile, working heart is well-established. However, the mechanism(s) by which the rates of long-chain fatty acid oxidation are controlled in the heart is (are) not as well understood as in the liver where the lipogenic substrate, malonyl-CoA, acts as a switch to partition fatty acids between synthesis and degradation [1]. Early studies in the working heart concluded that, at low levels of pressure development, rates of β-oxidation are limited by the disposal of acetyl-CoA through the citric acid cycle [2]. Recent evidence from the perfused, working rat heart [3] suggests that, similar to liver, the level of fatty acid oxidation directly reflects changes in activity of the tissue-specific acetyl-CoA carboxylase activity present in the cardiac myocyte. These results support the view that in the heart, the primary role for malonyl-CoA is the regulation of fatty acid flux through β-oxidation by inhibition of carnitine palmitoyltransferase I (CPT-I) on the outer mitochondrial membrane [4]. This situation may vary, however, depending upon the work load to the heart. When levels of cardiac work are increased, increases in fatty acylcarnitine and decreases in fatty acyl-CoA are observed concomittent with an acceleration of β-oxidation [2]. Since the long-chain acylcarnitine produced by CPT-I must be transported across the mitochondrial membrane to CPT-II in exchange for one molecule of carnitine from the matrix, these authors suggested that the increase in acylcarnitine accumulation observed at high work loads reflects a limitation in the carnitine-dependent pathway at the carnitine acylcarnitine translocase (CAT). The speculation that CAT may exert rate-limitation on fatty acylcarnitine oxidation under certain conditions has drawn support from observations that diabetic ketosis [5], and substrate-dependent activation [6] can up-regulate the rate of acylcarnitine translocation in liver and heart mitochondria, respectively. In the majority of these studies, it is likely that the expression of CAT activity is greatly influenced by variations in the matrix content of carnitine, the latter present at concentrations which are subsaturating under normal transport conditions [5, 7]. A decrement in matrix carnitine with aging [8,9] has been proposed to account for the decreased rates of CAT activity and palmitoylcarnitine oxidation in heart mitochondria from 24–30 month-old rats (Table 1). A related inability of palmitate to depress glucose extraction in the perfused working old rat heart suggests a direct physiological consequence of diminished acylcarnitine exchange on cardiac energy metabolism in aging [9]. The physiological importance of CAT has been further emphasized in clinical cases of genetic deficiencies reported in the translocase (see below). The functional ramifications of decreased or limiting CAT activity will be discussed below in relation to cardiac-specific effects.

“The expression of a limitation in carnitine acylcarnitine translocase activity relevant to human ischemic heart disease may be found only in those myocardial cells which are severely compromised and thus, may only be part of the end-stage sequellae of injury and cell death.”