Nox4 regulates InsP3 receptor-dependent Ca2+ release into mitochondria to promote cell survival.
EMBO J
; 39(19): e103530, 2020 10 01.
Article
en En
| MEDLINE
| ID: mdl-33001475
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Calcio
/
Señalización del Calcio
/
Miocitos Cardíacos
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Receptores de Inositol 1,4,5-Trifosfato
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NADPH Oxidasa 4
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Mitocondrias Cardíacas
Límite:
Animals
Idioma:
En
Revista:
EMBO J
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido