Role of the malate–aspartate shuttle on the metabolic response to myocardial ischemia

Abstract

The malate-aspartate (M-A) shuttle provides an important mechanism to regulate glycolysis and lactate metabolism in the heart by transferring reducing equivalents from cytosol into mitochondria. However, experimental characterization of the M-A shuttle has been incomplete because of the limitations in quantifying cytosolic and mitochondrial metabolites. In this study, we developed a multi-compartment model of cardiac metabolism with detailed presentation of the M-A shuttle to quantitatively predict non-observable fluxes and metabolite concentrations under normal and ischemic conditions in vivo. Model simulations predicted that the M-A shuttle is functionally localized to a subdomain that spans the mitochondrial and cytosolic spaces. With the onset of ischemia, the M-A shuttle flux rapidly decreased to a new steady-state in proportion to the reduction in blood flow. Simulation results suggest that the reduced M-A shuttle flux during ischemia was not due to changes in shuttle-associated enzymes and transporters. However, there was a redistribution of shuttle-associated metabolites in both cytosol and mitochondria. Therefore, the dramatic acceleration in glycolysis and the switch to lactate production that occur immediately after the onset of ischemia is mediated by reduced M-A shuttle flux through metabolite redistribution of shuttle associated-species across the mitochondrial membrane.Keywords malate-aspartate shuttle; metabolic compartmentation; mathematical modeling; myocardial ischemiaThe compartmentation of metabolites and enzymes between and within cytosol and mitochondria plays an important role in the regulation of energy metabolism in coordination with cell function. Although the metabolic processes in the cytosol and mitochondria are controlled locally, communication between them is important to achieve optimal substrate utilization, as well as to maintain a balance between ATP production and utilization. In Address correspondence to: Xin Yu, Sc.D., Wickenden 427, 10900 Euclid Avenue, Cleveland, OH 44106,, Email: xin.yu@case.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cardiomyocytes, cytosolic NADH is formed by glycolysis and lactate oxidation. To achieve maximal ATP production, cytosolic NADH must be transferred into the mitochondrial matrix to enter the electron transport chain, and cytosolic NAD + must be regenerated to maintain glycolytic flux and lactate conversion to pyruvate. It has been recognized that the inner mitochondrial membrane is impermeabl...

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“…Acceleration of glycolysis and lactate production during ischemia or hypoxia is mediated in part by reduced malate-aspartate shuttle flux along with redistribution of shuttle-associated metabolites. 29,30 In the current study, we did not perform compartmental analyses for these metabolites. However, we did observe anesthetic-related differences in overall concentration for amino acids, aspartate, and glutamate, which participate in NADH/NAD þ shuttling.…”

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“…The combination of glutamate and malate as substrate allows the study of the aspartate shuttle, which is the dominant pathway with rate of transporting electrons from NADH into mitochondria 10-fold or greater than that of NADH via a-glycerophosphate shuttle [31,37,38]. In cardiomyocytes, cytosolic NADH is formed by glycolysis and lactate oxidation and electrons from NADH must be transferred into the mitochondrial matrix to enter the electron transport chain in order to achieve maximal ATP production.…”

“…In cardiomyocytes, cytosolic NADH is formed by glycolysis and lactate oxidation and electrons from NADH must be transferred into the mitochondrial matrix to enter the electron transport chain in order to achieve maximal ATP production. This mechanism makes the malate-aspartate shuttle important to the heart for energy production [31]. Female gender predicts less myocardial glucose utilization and estrogen may be involved in lower glucose uptake and utilization because it decreases glucose oxidation, gluconeogenesis, and glycogenolysis in other organs and reduces glucose transporter 4 translocation to the cell surface, thereby inhibiting glucose uptake [39].…”

“…The combination of glutamate and malate as substrate produces NADH, source of electron for Complex I, thus allowing the study of the malate-aspartate shuttle [30]. In the heart, the malate-aspartate shuttle is the dominant pathway with the rate of transporting NADH into mitochondria 10-fold than NADH delivery via a-glycerophosphate shuttle [31]. Succinate is oxidized in Complex II (bypassing Complex I) and the addition of rotenone, an inhibitor of Complex I, allows assessing the activity of complex II.…”

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“…Specifically, it has been proposed that redistribution of shuttle-associated metabolites across the mitochondrial membrane is the mechanism responsible for a decrease in the malate-aspartate shuttle flux, impairing transport of cytosolic NADH, leading to a progressive NADH accumulation and lactate production [85] .…”