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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\u2010mitotic cells such as cardiomyocytes and neurons. Here, we show that stress\u2010induced upregulation of the ROS\u2010generating protein Nox4 at the ER\u2010mitochondria contact sites (MAMs) is a pro\u2010survival mechanism that inhibits calcium transfer through InsP\n                    <jats:sub>3<\/jats:sub>\n                    receptors (InsP\n                    <jats:sub>3<\/jats:sub>\n                    R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt\u2010dependent phosphorylation of InsP\n                    <jats:sub>3<\/jats:sub>\n                    R, thereby inhibiting calcium flux and mPT\u2010dependent necrosis. In hearts subjected to ischemia\u2013reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS\u2010generating protein mediates pro\u2010survival effects\u00a0through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT.\n                  <\/jats:p>","DOI":"10.15252\/embj.2019103530","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T05:52:31Z","timestamp":1597038751000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Nox4 regulates InsP3 receptor\u2010dependent Ca2+ release into mitochondria to promote cell survival"],"prefix":"10.1038","volume":"39","author":[{"given":"Matteo","family":"Beretta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celio XC","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Molenaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne D","family":"Hafstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5130-1845","authenticated-orcid":false,"given":"Chris CJ","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aram","family":"Revazian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Betteridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3099-526X","authenticated-orcid":false,"given":"Katrin","family":"Schr\u00f6der","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5137-7228","authenticated-orcid":false,"given":"Katrin","family":"Streckfu\u00df\u2010B\u00f6meke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H","family":"Doroshow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland A","family":"Fleck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung\u2010Ping","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod V","family":"Belousov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2021-8379","authenticated-orcid":false,"given":"Maddy","family":"Parsons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6547-0631","authenticated-orcid":false,"given":"Ajay M","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,10]]},"reference":[{"key":"BFEMBJ2019103530_CR1","doi-asserted-by":"crossref","first-page":"45935","DOI":"10.1074\/jbc.M406486200","volume":"279","author":"RK Ambasta","year":"2004","unstructured":"Ambasta RK, Kumar P, Griendling KK, Schmidt HH, Busse R, Brandes RP (2004) Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. 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