Hyperglycemia triggers RyR2-dependent alterations of mitochondrial calcium homeostasis in response to cardiac ischemia-reperfusion: Key role of DRP1 activation.

Autor:	Dubois M; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Boulghobra D; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Rochebloine G; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Pallot F; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Yehya M; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Bornard I; UR407 INRAE Pathologie Végétale, INRAE, 84140, Montfavet, France., Gayrard S; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Coste F; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Walther G; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Meyer G; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France., Gaillard JC; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 30200, Bagnols-sur-Cèze, France., Armengaud J; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 30200, Bagnols-sur-Cèze, France., Alpha-Bazin B; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 30200, Bagnols-sur-Cèze, France., Reboul C; LAPEC UPR-4278, Avignon Université, F-84000, Avignon, France. Electronic address: cyril.reboul@univ-avignon.fr.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Apr; Vol. 70, pp. 103044. Date of Electronic Publication: 2024 Jan 19.
DOI:	10.1016/j.redox.2024.103044
Abstrakt:	Hyperglycemia increases the heart sensitivity to ischemia-reperfusion (IR), but the underlying cellular mechanisms remain unclear. Mitochondrial dynamics (the processes that govern mitochondrial morphology and their interactions with other organelles, such as the reticulum), has emerged as a key factor in the heart vulnerability to IR. However, it is unknown whether mitochondrial dynamics contributes to hyperglycemia deleterious effect during IR. We hypothesized that (i) the higher heart vulnerability to IR in hyperglycemic conditions could be explained by hyperglycemia effect on the complex interplay between mitochondrial dynamics, Ca 2+ homeostasis, and reactive oxygen species (ROS) production; and (ii) the activation of DRP1, a key regulator of mitochondrial dynamics, could play a central role. Using transmission electron microscopy and proteomic analysis, we showed that the interactions between sarcoplasmic reticulum and mitochondria and mitochondrial fission were increased during IR in isolated rat hearts perfused with a hyperglycemic buffer compared with hearts perfused with a normoglycemic buffer. In isolated mitochondria and cardiomyocytes, hyperglycemia increased mitochondrial ROS production and Ca 2+ uptake. This was associated with higher RyR2 instability. These results could contribute to explain the early mPTP activation in mitochondria from isolated hearts perfused with a hyperglycemic buffer and in hearts from streptozotocin-treated rats (to increase the blood glucose). DRP1 inhibition by Mdivi-1 during the hyperglycemic phase and before IR induction, normalized Ca 2+ homeostasis, ROS production, mPTP activation, and reduced the heart sensitivity to IR in streptozotocin-treated rats. In conclusion, hyperglycemia-dependent DRP1 activation results in higher reticulum-mitochondria calcium exchange that contribute to the higher heart vulnerability to IR. Competing Interests: Declaration of competing interest The authors have no conflict of interest. (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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