Nox4 regulates InsP(3) receptor‐dependent Ca(2+) release into mitochondria to promote cell survival

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(3)R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt‐dependent phosphorylation of InsP(3)R, 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.