title: Impaired cytosolic NADH shuttling and elevated UCP3 contribute to inefficient citric acid cycle flux support of postischemic cardiac work in diabetic hearts.
abstract: Diabetic hearts are subject to more extensive ischemia/reperfusion (ISC/REP) damage. This study examined the efficiency of citric acid cycle (CAC) flux and the transfer of cytosolic reducing equivalents into the mitochondria for oxidative support of cardiac work following ISC/REP in hearts of c57bl/6 (NORM) and type 2 diabetic, db/db mouse hearts. Flux through the CAC and malate-aspartate shuttle (MA) were monitored via dynamic (13)C NMR of isolated hearts perfused with (13)C palmitate+glucose. MA flux was lower in db/db than NORM. Oxoglutarate malate carrier (OMC) was elevated in the db/db heart, suggesting a compensatory response to low NADHc. Baseline CAC flux per unit work (rate-pressure-product, RPP) was similar between NORM and db/db, but ISC/REP reduced the efficiency of CAC flux/RPP by 20% in db/db. ISC/REP also increased UCP3 transcription, indicating potential for greater uncoupling. Therefore, ISC/REP induces inefficient carbon utilization through the CAC in hearts of diabetic mice due to the combined inefficiencies in NADHc transfer per OMC content and increased uncoupling via UCP3. Ischemia and reperfusion exacerbated pre-existing mitochondrial defects and metabolic limitations in the cytosol of diabetic hearts. These limitations and defects render diabetic hearts more susceptible to inefficient carbon fuel utilization for oxidative energy metabolism.
authors.affiliation: Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA.
authors.forename: Natasha H
authors.initials: NH
authors.lastname: Banke
authors.affiliation: Center for Cardiovascular Research and Department of Physiology and Biophysics, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA. Electronic address: dougl@uic.edu.
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002352:Carrier Proteins / Q000378:metabolism; D002952:Citric Acid Cycle; D003600:Cytosol / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D007473:Ion Channels / Q000378:metabolism*; D008293:Malates / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D010477:Perfusion; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D008293:Malates; D024101:Mitochondrial Proteins; D047493:PPAR alpha; C000604393:Ucp3 protein, mouse; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D009243:NAD; C066909:2-oxoglutarate-malate carrier protein; D001224:Aspartic Acid; C030298:malic acid
keywords: Mitochondria; Oxoglutarate–malate carrier; Reducing equivalents; Uncoupling protein; db/db mouse malate–aspartate shuttle