Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis

Oncogene. 2008 Jan 10;27(3):285-99. doi: 10.1038/sj.onc.1210638. Epub 2007 Aug 13.


The accumulation of Ca2+ in the mitochondrial matrix can stimulate oxidative phosphorylation, but can also, at high Ca2+ concentrations, transmit and amplify an apoptotic signal. Here, we characterized the capacity of physiological stimuli (for example, histamine and inositol-1,4,5-triphosphate) and inducers of endoplasmic reticulum (ER) stress (for example, A23187, thapsigargin and tunicamycin) to release Ca2+ from ER stores, induce mitochondrial Ca2+ accumulation, and trigger cell death in human cervix and colon carcinoma cell lines. Sustained Ca2+ accumulation in the mitochondrial matrix induced by ER stress triggered signs of proapoptotic mitochondrial alteration, namely permeability transition, dissipation of the electrochemical potential, matrix swelling, relocalization of Bax to mitochondria and the release of cytochrome c and apoptosis-inducing factor from mitochondria. In contrast, rapid and transient accumulation of Ca2+ induced by physiological stimuli failed to promote mitochondrial permeability transition and to affect cell viability. The specificity of this apoptosis pathway was validated in cells using a panel of pharmacological agents that chelate Ca2+ (BAPTA-AM) or inhibit inositol-1,4,5-trisphosphate receptor (IP(3)R; 2-aminoethoxydiphenyl borate), voltage-dependent anion channel (VDAC) (4,4'-diisothiocyanatostilbene-2,2'-disulfonate, NADH), the permeability transition pore (cyclosporin A and bongkrekic acid), caspases (z-VAD-fmk) and protein synthesis (cycloheximide). Finally, we designed an original cell-free system in which we confronted purified mitochondria and ER vesicles, and identified IP(3)R, VDAC and the permeability transition pore as key proteins in the ER-triggered proapoptotic mitochondrial membrane permeabilization process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Azirines / metabolism
  • Calcium / metabolism*
  • Calcium Signaling*
  • Cell Line, Tumor
  • Cell-Free System
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Histamine / pharmacology
  • Humans
  • Inositol 1,4,5-Trisphosphate / pharmacology
  • Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Swelling
  • Permeability / drug effects
  • Phosphatidylcholines / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Voltage-Dependent Anion Channels / metabolism


  • Azirines
  • Inositol 1,4,5-Trisphosphate Receptors
  • Phosphatidylcholines
  • Proto-Oncogene Proteins c-bcl-2
  • Voltage-Dependent Anion Channels
  • Histamine
  • Inositol 1,4,5-Trisphosphate
  • 1-palmitoyl-2-(10-(4-((trifluoromethyl)diazirinyl)phenyl)-8-oxadecanoyl)-sn-glycero-3-phosphocholine
  • Calcium