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Nox4 regulates InsP3 receptor‐dependent Ca2+ release into mitochondria to promote cell survival

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Matteo Beretta, Celio Xc Santos, Chris Molenaar, Anne D Hafstad, Chris Cj Miller, Aram Revazian, Kai Betteridge, Katrin Schröder, Katrin Streckfuß-Bömeke, James H Doroshow, Roland A Fleck, Tsung-Ping Su, Vsevolod V Belousov, Maddy Parsons, Ajay M Shah

Original languageEnglish
Article numbere103530
Number of pages20
JournalThe EMBO journal
Issue number19
Early online date10 Aug 2020
Accepted/In press10 Aug 2020
E-pub ahead of print10 Aug 2020
Published1 Oct 2020


King's Authors


Cells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post-mitotic cells such as cardiomyocytes and neurons. Here, we show that stress-induced upregulation of the ROS-generating protein Nox4 at the ER-mitochondria contact sites (MAMs) is a pro-survival mechanism that inhibits calcium transfer through InsP 3 receptors (InsP 3R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP 3R, thereby inhibiting calcium flux and mPT-dependent necrosis. In hearts subjected to ischemia–reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS-generating protein mediates pro-survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT.

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