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

TY - JOUR

T1 - Nox4 regulates InsP3 receptor‐dependent Ca2+ release into mitochondria to promote cell survival

AU - Beretta, Matteo

AU - Santos, Celio Xc

AU - Molenaar, Chris

AU - Hafstad, Anne D

AU - Miller, Chris Cj

AU - Revazian, Aram

AU - Betteridge, Kai

AU - Schröder, Katrin

AU - Streckfuß-Bömeke, Katrin

AU - Doroshow, James H

AU - Fleck, Roland A

AU - Su, Tsung-Ping

AU - Belousov, Vsevolod V

AU - Parsons, Maddy

AU - Shah, Ajay M

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

KW - InsP receptor

KW - NADPH oxidase-4

KW - calcium signaling

KW - cell death

KW - mitochondria-associated membrane

UR - http://www.scopus.com/inward/record.url?scp=85089160208&partnerID=8YFLogxK

U2 - 10.15252/embj.2019103530

DO - 10.15252/embj.2019103530

M3 - Article

C2 - 33001475

SN - 0261-4189

VL - 39

JO - The EMBO journal

JF - The EMBO journal

IS - 19

M1 - e103530

ER -