Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis
Abstract
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 (cycl…
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Thapsigargin-induced Ca2+ transfer from the ER to mitochondria depends on IP3R in the ER and VDACs on the outer mitochondrial membrane.
“Furthermore, thapsigargin-induced Ca2+ transfer from the ER to mitochondria depends on IP3R in the ER and VDACs on the outer mitochondrial membrane [93, 94].”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [93]
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“In our cell-free system, we also used different inhibitors of VDAC to block the Ca2þ m entry through the OMM, as described earlier by Gincel et al. (2001).”
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- Authors
- Deniaud, A., Sharaf el dein, O., Maillier, E., Poncet, D., Kroemer, G., Lemaire, C., & Brenner, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Brenner, C
- Venue
- Oncogene
- Published
- 2007-08-13
- Volume
- 27
- Issue
- 3
- Pages
- 285-299
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2031591517
- Cited by
- 586
- References
- 4
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 23 · 2023: 30 · 2022: 32 · 2021: 30 · 2020: 33 · 2019: 34 · 2018: 37 · 2017: 34 · 2016: 40 · 2015: 33 · 2014: 38 · 2013: 29 · 2012: 36
- FWCI
- 10.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- endoplasmic reticulum stress, mitochondrial permeability transition, mitochondrial outer membrane permeabilization, apoptosis, mitochondrial calcium accumulation, IP3 receptor, voltage-dependent anion channel, mitochondrial permeability transition pore, Bax, cytochrome c release, apoptosis-inducing factor, ER-mitochondria communication, cell-free system, cervical cancer cells, colon cancer cells, thapsigargin, tunicamycin, cyclosporine
- MeSH terms
- Azirines, Calcium, Cell-Free System, Endoplasmic Reticulum, Histamine, Humans, Mitochondrial Swelling, Permeability, Phosphatidylcholines, Inositol 1,4,5-Trisphosphate, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Calcium Signaling, Cell Line, Tumor, Voltage-Dependent Anion Channels, Mitochondrial Membranes, Membrane Potential, Mitochondrial, Inositol 1,4,5-Trisphosphate Receptors
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