Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways

Jenelle M. Timmins, Lale Ozcan, Tracie A. Seimon, Gang Li, Cristina Malagelada, Johannes Backs, Thea Backs, Rhonda Bassel-Duby, Eric N. Olson, Mark E. Anderson, Ira Tabas

Research output: Contribution to journalArticle

288 Scopus citations

Abstract

ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ) and JNK. Remarkably, CaMKIIγ was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKIIγ-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)2925-2941
Number of pages17
JournalJournal of Clinical Investigation
Volume119
Issue number10
DOIs
StatePublished - Oct 1 2009

ASJC Scopus subject areas

  • Medicine(all)

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    Timmins, J. M., Ozcan, L., Seimon, T. A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E. N., Anderson, M. E., & Tabas, I. (2009). Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. Journal of Clinical Investigation, 119(10), 2925-2941. https://doi.org/10.1172/JCI38857