Mildronate: Mechanisms of action and prospects for correction of pathologic states

Abstract

The energy metabolism of fatty acids (FA) is attributed to their intramitochondrial [?,-oxidation. FA with number of carbon atoms less than 12 penetrate into mitochondria by a camitine-independent pathway. Carnitine-y-trimethylamino[3-hydroxybutyrate is needed for the oxidation of long-chain FA [1, 2]. Long-chain FA are activated under the effect of acyI-CoA synthetase at the external membrane of mitochondria to form long-chain acyI-CoA, which penetrates the outer surface of the internal membrane of mitochondria where carnitine acyltransferase-I catalyzes (in the presence of free carnitine) the formation of long-chain acylcarnitine from awlCoA. This metabolite, under the effect of carnitine-acylcarnitine translocase, localized in the internal membrane of mitochondria, penetrates the mitochondrial matrix, where carnitine acyltransferase-II located at the inner surface of the internal membrane of the mitochondria tends to form longchain acyl-CoA. The latter is subjected to 13-oxidation. Released free carnitine, under the effect of camitine-acylcarnitine translocase, is transported to the external membrane of mitochondria, thus closing the so-called carnitine cycle [1]. 13-Oxidation of FA is the main pathway of myocardium energy supply under normal conditions [3, 4], the high energy efficiency of oxidation being favorable for myocardial contractility. However, in homeostasis disorders the advantageous use of FA by the myocardium can be transformed into one of the main prerequisites of pathological process. Both ischemia and a decrease in the partial oxygen pressure result in suppressing oxygen-dependent processes, including oxidation of FA in the cardiomyocytes, because of disorders in their intramitochondrial metabolism [5, 6], and processes of FA activation and FA transport to the mitochondrial matrix. An increase in the content of free FA in blood is observed in patients with ischemia, which is attributed to FA release from adipose depots under the effect of hormone-sensitive triglyceride lipase [7, 8]. Accumulation of free FA and the products of their metabolic activation (long-chain acyl-CoA and acylcamitine)