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

Mathilde Dubois (1) , Doria Boulghobra (1) , Gilles Rochebloine (1) , Florian Pallot (1) , Marc Yehya (1) , Isabelle Bornard (2) , Sandrine Gayrard (1) , Florence Coste (1) , Guillaume Walther (1) , Gregory Meyer (1) , Jean-Charles Gaillard (3) , Jean Armengaud (3) , Béatrice Alpha-Bazin (3) , Cyril Reboul (1)

1 LaPEC - EA4278 Laboratoire de Pharm-Ecologie Cardiovasculaire
2 PV - Unité de Pathologie Végétale
3 MTS - Médicaments et Technologies pour la Santé

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.

Keywords: Mitochondria; Calcium homeostasis; Hyperglycemia; Ischemia-reperfusion

Domains: Human health and pathology; Health

Mathilde Dubois, Doria Boulghobra, Gilles Rochebloine, Florian Pallot, Marc Yehya, et al.. Hyperglycemia triggers RyR2-dependent alterations of mitochondrial calcium homeostasis in response to cardiac ischemia-reperfusion: Key role of DRP1 activation. Redox Biology, 2024, 70, pp.103044. ⟨10.1016/j.redox.2024.103044⟩. ⟨hal-04416349⟩