Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways
Jenelle M. Timmins, … , Mark E. Anderson, Ira Tabas
Jenelle M. Timmins, … , Mark E. Anderson, Ira Tabas
Published September 8, 2009
Citation Information: J Clin Invest. 2009;119(10):2925-2941. https://doi.org/10.1172/JCI38857.
View: Text | PDF
Research Article Cell biology

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

  • Text
  • PDF
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.

Authors

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

×

Figure 6

ER stress in macrophages leads to the accumulation of calcium in the mitochondria.

Options: View larger image (or click on image) Download as PowerPoint
ER stress in macrophages leads to the accumulation of calcium in the mit...
(A) Macrophages were plated on 25-mm coverslips and grown to confluency. The cells were incubated under control or cholesterol-loading conditions for 1 hour and stained with 5 μM Fura-2 for 30 minutes. The cells were then rinsed in medium and examined by fluorescence microscopy, where calcium fluorescence was measured every second. FCCP (1 μM), a mitochondrial uncoupler, and ionomycin (10 μM) were added at the indicated times to release mitochondrial and overall intracellular calcium stores, respectively. (B) Macrophages were treated with medium alone as control, with 0.25 μM thapsigargin for 1 hour, or under cholesterol-loading conditions for 2 or 4 hours. At the end of each incubation, 10 μM Rhod-2, a mitochondrial-specific fluorescent calcium dye, was added to the media, and the cells were incubated on ice for 1 hour at 4°C. The cells were then washed and incubated for an additional 5 hours with thapsigargin or under cholesterol-loading conditions, such that total incubation time for thapsigargin was 5 hours and for cholesterol 5 or 7 hours. At the end of the incubation period, the cells were visualized using confocal microscopy and imaged as described in Methods. Scale bar: 10 μm. Fluorescence intensity for approximately 100 cells was measured for each treatment group. Differing symbols indicate P < 0.01; identical symbols indicate differences that are not significant.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts