Role of the malate–aspartate shuttle on the metabolic response to myocardial ischemia
- 30 May 2008
- journal article
- Published by Elsevier BV in Journal of Theoretical Biology
- Vol. 254 (2), 466-475
- https://doi.org/10.1016/j.jtbi.2008.05.033
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 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
This publication has 79 references indexed in Scilit:
- Detection of allergen composition and in vivo immunogenicity of depigmented allergoids of Betula albaClinical and Experimental Allergy, 2009
- The Crystal Structure of the Major Cat Allergen Fel d 1, a Member of the Secretoglobin FamilyPublished by Elsevier BV ,2003
- IgE antibodies to recombinant forms of Fel d I: Dichotomy between fluid-phase and solid-phase binding studiesJournal of Allergy and Clinical Immunology, 1995
- Enhanced immunoreactivity and preferential heterodimer formation of reassociated Fel d I recombinant chainsMolecular Immunology, 1995
- Role of the Major Allergen (Fel d I) in Patients Sensitized to Cat AllergensInternational Archives of Allergy and Immunology, 1993
- Structure of the Major Cat Allergen Fel d I in Different Allergen Sources: An Immunoblotting Analysis with Monoclonal Antibodies against Denatured Fel d I and Human IgEInternational Archives of Allergy and Immunology, 1992
- Controlled evaluation of allergoid in the immunotherapy of ragweed hay feverJournal of Allergy and Clinical Immunology, 1982
- Studies on allergoids from naturally occurring allergens IV. Efficacy and safety of long-term allergoid treatment of ragweed hay feverJournal of Allergy and Clinical Immunology, 1981
- Control of the transport of reducing equivalents across the mitochondrial membrane in perfused rat heartJournal of Molecular and Cellular Cardiology, 1971
- Intramitochondrial localization of palmityl-CoA dehydrogenase, β-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase in guinea-pig heartBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1971