Zn2+ protect cardiac H9c2 cells from endoplasmic reticulum stress by preventing mPTP opening through MCU

Zn2+ regulates endoplasmic reticulum stress (ERS) and is essential for myocardial protection through gating the mitochondrial permeability transition pore (mPTP). However, the underlining mechanism of the mPTP opening remains uncertain. Cells under sustained ERS induce unfolded protein responses (UPR) and cell apoptosis. Glucose regulatory protein 78 (GRP 78) and glucose regulatory protein 94 (GRP 94) are marker proteins of ERS and regulate the onset of apoptosis through the endoplasmic reticulum signaling pathway. We found tunicamycin (TM) treatment activates ERS and significantly increases intracellular Ca2+ and mitochondrial reactive oxygen species (ROS) levels in H9c2 cardiomyocyte cells. Zn2+ markedly decreased protein level of GRP 78/94 and suppressed intracellular Ca2+ and ROS elevation. Mitochondrial calcium uniporter (MCU) is an important Ca2+ transporter protein, through which Zn2+ enter mitochondria. MCU inhibitor ruthenium red (RR) or siRNA significantly reversed the Zinc effect on GRP 78, mitochondrial Ca2+ and ROS. Additionally, Zn2+ prevented TM-induced mPTP opening and decreased mitochondrial Ca2+ concentration, which were blocked through inhibiting or knockdown MCU with siRNA. In summary, our study suggests that Zn2+ protected cardiac ERS by elevating Ca2+ and closing mPTP through MCU. •Zn2+ is critical for myocardial protection by reducing endoplasmic reticulum stress (ERS) and mitochondrial permeability transition pore (mPTP) opening.•However, the gating mechanism of the mPTP remains unclear.•We found Zn2+ markedly inhibited the expression of glucose regulated protein 78 (GRP 78) and glucose regulated protein 94 (GRP 94), suppressed Ca2+ and ROS elevation in tunicamycin treated H9c2 cells.•Furthermore, mitochondrial calcium uniporter (MCU) is a novel Zn2+ transporter essential for myocardial protection.•In summary, our data suggest that Zn2+ protected cardiac cells from ERS by Ca2+ and preventing mPTP opening through MCU.