Nox4 Regulates Insp(3) Receptor-Dependent Ca2+ 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 ofRCDis 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 theROS-generating protein Nox4 at theER-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 theMAMof 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.