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Zinc improves mitochondrial respiratory function and prevents mitochondrial ROS generation at reperfusion by phosphorylating STAT3 at Ser.

Zinc improves mitochondrial respiratory function and prevents mitochondrial ROS generation at reperfusion by phosphorylating STAT3 at Ser.
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Zhang G, Sheng M, Wang J, Teng T, Sun Y, Yang Q, Xu Z,


Zhang G, Sheng M, Wang J, Teng T, Sun Y, Yang Q, Xu Z, (click to view)

Zhang G, Sheng M, Wang J, Teng T, Sun Y, Yang Q, Xu Z,

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Journal of molecular and cellular cardiology 2018 03 29() pii S0022-2828(18)30091-9
Abstract

Serine 727 (Ser) phosphorylation of STAT3 plays a role in the regulation of mitochondrial respiration. This study aimed to test if zinc could regulate mitochondrial respiration through phosphorylation of STAT3 at Serin the setting of ischemia/reperfusion in the heart. Under normoxic conditions, treatment of isolated rat hearts with ZnClincreased cytosolic STAT3 phosphorylation at Serfollowed by phospho-STAT3 translocation to mitochondria. In isolated rat hearts subjected to 30 min regional ischemia followed by 20 min of reperfusion, ZnClgiven 5 min before the onset of reperfusion also increased mitochondrial phospho-STAT3. ZnClenhanced ERK phosphorylation and PD98059 reversed the effect of ZnClon STAT3 phosphorylation. ZnClimproved the mitochondrial oxidative phosphorylation at reperfusion. This effect was abolished by STAT3S727A, a mutant in which Seris replaced with alanine, in H9c2 cells subjected to hypoxia/reoxygenation. In addition, ZnClincreased the mRNA level of the complex I subunit ND6, which was also reversed by STAT3S727A. Moreover, ZnClattenuated mitochondrial ROS generation and dissipation of mitochondrial membrane potential (ΔΨm) at reoxygenation through Serphosphorylation. Finally, ZnClsuppression of succinate dehydrogenase (SDH) activity upon the onset of reperfusion was nullified by the Sermutation. In conclusion, zinc improves cardiac oxidative phosphorylation and inhibits mitochondrial ROS generation at reperfusion by increasing mitochondrial STAT3 phosphorylation at Servia ERK. The preservation of ND6 mtDNA and the inhibition of SDH activity may account for the role of STAT3 in the beneficial action of zinc on the mitochondrial oxidative phosphorylation and ROS generation at reperfusion.

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