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Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence

Author

Listed:
  • Clotilde Wiel

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Hélène Lallet-Daher

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Delphine Gitenay

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Baptiste Gras

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Benjamin Le Calvé

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Arnaud Augert

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Mylène Ferrand

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • Natalia Prevarskaya

    (Inserm U1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies)

  • Hélène Simonnet

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • David Vindrieux

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

  • David Bernard

    (Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab
    CNRS UMR5286
    Centre Léon Bérard
    Université de Lyon)

Abstract

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.

Suggested Citation

  • Clotilde Wiel & Hélène Lallet-Daher & Delphine Gitenay & Baptiste Gras & Benjamin Le Calvé & Arnaud Augert & Mylène Ferrand & Natalia Prevarskaya & Hélène Simonnet & David Vindrieux & David Bernard, 2014. "Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4792
    DOI: 10.1038/ncomms4792
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    Cited by:

    1. Valerio Farfariello & Dmitri V. Gordienko & Lina Mesilmany & Yasmine Touil & Emmanuelle Germain & Ingrid Fliniaux & Emilie Desruelles & Dimitra Gkika & Morad Roudbaraki & George Shapovalov & Lucile No, 2022. "TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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