[Retracted] Melatonin Attenuates Cardiac Ischemia‐Reperfusion Injury through Modulation of IP3R‐Mediated Mitochondria‐ER Contact

Abstract

Although the interplay between mitochondria and ER has been identified as a crucial regulator of cellular homeostasis, the pathogenic impact of alterations in mitochondria-ER contact sites (MERCS) during myocardial postischemic reperfusion (I/R) injury remains incompletely understood. Therefore, in our study, we explored the beneficial role played by melatonin in protecting cardiomyocytes against reperfusion injury via stabilizing mitochondria-ER interaction. In vitro exposure of H9C2 rat cardiomyocytes to hypoxia/reoxygenation (H/R) augmented mitochondrial ROS synthesis, suppressed both mitochondrial potential and ATP generation, and increased the mitochondrial permeability transition pore (mPTP) opening rate. Furthermore, H/R exposure upregulated the protein content of CHOP and caspase-12, two markers of ER stress, and enhanced the transcription of main MERCS tethering proteins, namely, Fis1, BAP31, Mfn2, and IP3R. Interestingly, all the above changes could be attenuated or reversed by melatonin treatment. Suggesting that melatonin-induced cardioprotection works through normalization of mitochondria-ER interaction, overexpression of IP3R abolished the protective actions offered by melatonin on mitochondria-ER fitness. These results expand our knowledge on the cardioprotective actions of melatonin during myocardial postischemic reperfusion damage and suggest that novel, more effective treatments for acute myocardial reperfusion injury might be achieved through modulation of mitochondria-ER interaction in cardiac cells.

The Regulatory Roles of Mitochondrial Calcium and the Mitochondrial Calcium Uniporter in Tumor Cells

“…In addition, an overload of Ca 2+ leading to oxidative metabolism impairment and ROS overproduction [ 123 ]. Previous studies have suggested that under oxygen stress, ROS produced by mitochondria will cause membrane lipid peroxidation and changes in mitochondrial function, resulting in the release of Ca 2+ and apoptosis of mitochondria [ 124 ]; (3) ROS can regulate IP 3 R production and affect Ca 2+ release from the ER into mitochondria [ 125 ]; (4) ROS can also affect the sarcoplasmic reticulum Ca 2+ pump and inhibit intracellular or extracellular ER Ca 2+ transfer by inhibiting the Ca 2+ -ATPase pump [ 126 ]; (5) Both ROS and Ca 2+ can induce MPTP opening. On the other hand, MPTP opening leads to a large increase in ROS [ 127 ].…”

Mitochondria-Endoplasmic Reticulum Contacts: The Promising Regulators in Diabetic Cardiomyopathy

“…Application of melatonin inhibits IP3R, stabilizing the physical contacts between mitochondria and ER, and thus improving mitochondrial function and reducing cardiomyocytes damage. Moreover, some other MAM markers, Fis1, BAP31, and MFN2, were also inhibited by melatonin [ 100 ]. These data suggest that melatonin-induced cardioprotective effect is mediated via normalization of mitochondria-ER interaction.…”

The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells

“…Remarkably, melatonin exerts cardioprotective effects in several cardiovascular disorders (Zhou et al, 2018). Furthermore, melatonin is protective against cardiomyocyte I/R injury by stabilizing MERCs, modulating gene expression, and mediating mitochondrial protection by preventing the positive regulation of the IP3R in I/R (Li et al, 2021).…”