Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence
Open accessAbstract
Senescence is involved in various pathophysiological conditions. Besides loss of retinoblastoma and p53 pathways, little is known about other pathways involved in senescence. Here we identify two calcium channels; inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) (also known as inositol 1,4,5-triphosphate receptor 2 (IP3R2)) and mitochondrial calcium uniporter (MCU) as new senescence regulators in a loss-of-function genetic screen. We show that loss of ITPR2, known to mediate endoplasmic reticulum (ER) calcium release, as well as loss of MCU, necessary for mitochondrial calcium uptake, enable escape from oncogene-induced senescence (OIS). During OIS, ITPR2 triggers calcium release from the ER, followed by mitochondrial calcium accumulation through MCU channels. Mitochondrial calcium accumulation leads to a subsequent decrease in mitochondrial membrane potential, reactive oxygen species accumulation and senescence. This ER-mitochondria calcium transport is not restricted to OIS, but is also involved in replicative senescence. Our results show a functional role of calcium release by the ITPR2 channel and its subsequent accumulation in the mitochondria.
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ITPR2 and MCU are novel regulators of the senescence program by increasing Ca2+ uptake.
“Wiel et al., identified two calcium channels, inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) localized in the ER and the mitochondrial calcium uniporter (MCU), as novel regulators of senescence program by increasing Ca2+ uptake”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [178]
During OIS and replicative senescence, ITPR2 triggers Ca2+ release from the endoplasmic reticulum, with subsequent mitochondrial Ca2+ accumulation via MCU channel, leading to reduced mitochondrial membrane potential, ROS accumulation, and senescence.
“During OIS and replicative senescence, ITPR2 triggers Ca2+ release from the endoplasmic reticulum (ER), with subsequent mitochondrial Ca2+ accumulation via MCU channel, leading to reduced mitochondrial membrane potential, ROS accumulation, and senescence”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [178]
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References 49 · Cited by 231
- Authors
- Wiel, C., Lallet-Daher, H., Gitenay, D., Gras, B., Le Calvé, B., Augert, A., Ferrand, M., Prevarskaya, N., Simonnet, H., Vindrieux, D., & Bernard, D.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Bernard, David
- ORCID
- Venue
- Nature Communications
- Published
- 2014-05-06
- Volume
- 5
- Issue
- 1
- Pages
- 3792-3792
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2021810546
- Cited by
- 231
- References
- 49
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 28 · 2023: 30 · 2022: 22 · 2021: 19 · 2020: 17 · 2019: 14 · 2018: 19 · 2017: 15 · 2016: 9 · 2015: 9 · 2014: 3
- FWCI
- 7.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Repository of the University of Namur (submittedVersion, other-oa)
- Funders
- Fondation ARC pour la Recherche sur le Cancer
- Fondation de France
- Institut National Du Cancer
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- cellular senescence, oncogene-induced senescence, replicative senescence, ITPR2, IP3R2, mitochondrial calcium uniporter, mitochondrial calcium accumulation, endoplasmic reticulum calcium release, calcium signaling, reactive oxygen species, mitochondrial membrane potential
- MeSH terms
- Calcium, Endoplasmic Reticulum, Humans, Mitochondria, Oncogenes, Cellular Senescence, Oxidative Stress, Membrane Potential, Mitochondrial, Inositol 1,4,5-Trisphosphate Receptors
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