Nox4 regulates InsP3 receptor-dependent Ca2+ release into mitochondria to promote cell survival.
Matteo BerettaCelio Xc SantosChris MolenaarAnne D HafstadChristopher C J MillerAram RevazianKai BetteridgeKatrin SchroderKatrin Streckfuß-BömekeJames H DoroshowRoland A FleckTsung-Ping SuVsevolod V BelousovMaddy ParsonsAjay M ShahPublished in: The EMBO journal (2020)
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.
Keyphrases
- cell death
- cell cycle arrest
- reactive oxygen species
- induced apoptosis
- stress induced
- signaling pathway
- endoplasmic reticulum
- oxidative stress
- public health
- cell proliferation
- acute myocardial infarction
- dna damage
- heart failure
- transcription factor
- pi k akt
- poor prognosis
- endoplasmic reticulum stress
- risk assessment
- coronary artery disease
- percutaneous coronary intervention
- weight gain
- free survival
- physical activity
- acute coronary syndrome
- body mass index
- amino acid
- climate change
- human health