학술논문
Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.
Document Type
Academic Journal
Author
Sánchez-Pérez P; Centro de Biología Molecular 'Severo Ochoa' (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain.; Mata A; Centro de Biología Molecular 'Severo Ochoa' (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain.; Torp MK; Centro de Biología Molecular 'Severo Ochoa' (CSIC/UAM), 28049, Madrid, Spain; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway.; López-Bernardo E; Centro de Biología Molecular 'Severo Ochoa' (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain.; Heiestad CM; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway.; Aronsen JM; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway; Bjørknes College, 0456, Oslo, Norway.; Molina-Iracheta A; Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029, Madrid, Spain.; Jiménez-Borreguero LJ; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain; Servicio de Cardiología, Hospital Universitario de La Princesa, 28006, Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029, Madrid, Spain.; García-Roves P; Department of Physiological Sciences, Universitat de Barcelona, 08907, Barcelona, Spain; Nutrition, Metabolism and Gene Therapy Group, Diabetes and Metabolism Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain.; Costa ASH; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Center, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.; Frezza C; MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Center, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK.; Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK.; Stenslokken KO; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PB1110, N-0317, Oslo, Norway.; Cadenas S; Centro de Biología Molecular 'Severo Ochoa' (CSIC/UAM), 28049, Madrid, Spain; Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006, Madrid, Spain. Electronic address: scadenas@cbm.csic.es.
Source
Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE
Subject
Language
English
Abstract
Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site I Q in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.
Competing Interests: Declaration of competing interest The authors declare that no competing financial interests exist in relation to this manuscript.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that no competing financial interests exist in relation to this manuscript.
(Copyright © 2023 Elsevier Inc. All rights reserved.)