| First Author | Beretta M | Year | 2020 |
| Journal | EMBO J | Volume | 39 |
| Issue | 19 | Pages | e103530 |
| PubMed ID | 33001475 | Mgi Jnum | J:309277 |
| Mgi Id | MGI:6714386 | Doi | 10.15252/embj.2019103530 |
| Citation | Beretta M, et al. (2020) Nox4 regulates InsP3 receptor-dependent Ca(2+) release into mitochondria to promote cell survival. EMBO J 39(19):e103530 |
| abstractText | 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 InsP3 receptors (InsP3 R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP3 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. |
