Brief Reviews The Metabolic Significance of the Malate-Aspartate Cycle in Heart By Brian Safer

• Under physiological conditions, the energy requirements of the heart are met primarily by the oxidation of fatty acids, glucose, and lactate (1, 2). Initially, during the metabolism of glucose and lactate, the coenzyme NAD is reduced to NADH and pyruvate is formed in the cytosolic compart-ment1 of the myocardial cell. Subsequent entry of pyruvate into the mitochondria for oxidative me-tabolism in the citric acid cycle requires an equiva-lent oxidation of cytosolic NADH by the mitochon-drial electron transport chain, which regenerates NAD. However, direct transfer of the reduced co-enzyme NADH to the respiratory chain is pre-vented by a selective permeability barrier across the inner mitochondrial membrane to NADH as well as other metabolic intermediates (3, 4). Al-though several indirect shuttle mechanisms have been proposed (5-7), current evidence indicates that the reducing equivalents formed in the re-duction of cytosolic NAD to NADH are indirectly carried into the mitochondrial compartment of the heart and other tissues by metabolic anions of the malate-aspartate cycle (8-11). In addition, interac-tion of the malate-aspartate cycle with the citric acid cycle, through key common metabolic inter-mediates, may provide a major mechanism by which coordination of mitochondrial and cytosolic energy metabolism is achieved in the myocardiu