Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3

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 fa...

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Published in:Free radical biology & medicine 2023-08, Vol.205, p.244-261
Main Authors: Sánchez-Pérez, Patricia, Mata, Ana, Torp, May-Kristin, López-Bernardo, Elia, Heiestad, Christina M., Aronsen, Jan Magnus, Molina-Iracheta, Antonio, Jiménez-Borreguero, Luis J., García-Roves, Pablo, Costa, Ana S.H., Frezza, Christian, Murphy, Michael P., Stenslokken, Kåre-Olav, Cadenas, Susana
Format: Article
Language:eng ; nor
Subjects:
Animals
Coronary Artery Disease - metabolism
Energy Metabolism
Fatty Acids - metabolism
Infarction - complications
Infarction - metabolism
Ischemia - metabolism
Ischemia-reperfusion injury
Mice
Mitochondria - metabolism
Mitochondrial respiration
Mitochondrial structure
Myocardial Ischemia - metabolism
Myocardial Reperfusion Injury - genetics
Myocardial Reperfusion Injury - metabolism
Myocytes, Cardiac - metabolism
Oxidative Stress
Reperfusion
Superoxides - metabolism
UCP3 (uncoupling protein 3)
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Summary: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 IQ 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. [Display omitted] •UCP3 deficiency increases infarct size after in vivo and ex vivo myocardial IR.•UCP3 knockout and wild-type hearts have a similar metabolic response to IR.•S1QEL limits the infarct size in UCP3 knockout hearts after myocardial IR.•Myocardial IR impairs fatty acid oxidation and complex I (but not complex II) activity.•UCP3 deficiency severely affects cardiac mitochondrial ultrastructure after IR.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2023.05.014