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Updated: Apr 30, 2026

Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms
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Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms

Published on: July 7, 2011

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

Clotilde Wiel1, Hélène Lallet-Daher1, Delphine Gitenay2

  • 11] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France [5].

Nature Communications
|May 7, 2014
PubMed

Insights

New research identifies inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) and mitochondrial calcium uniporter (MCU) as key regulators of cellular senescence. Their dysfunction allows cells to escape senescence, impacting various diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Cellular senescence plays a role in various pathophysiological conditions.
  • While retinoblastoma and p53 pathways are known regulators of senescence, other involved pathways remain largely uncharacterized.

Purpose of the Study:

  • To identify novel regulators of cellular senescence beyond the well-known pathways.
  • To investigate the role of calcium channels in senescence, particularly in oncogene-induced senescence (OIS).

Main Methods:

  • A loss-of-function genetic screen was employed to identify new senescence regulators.
  • The study focused on two calcium channels: inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) and mitochondrial calcium uniporter (MCU).
  • Experiments involved analyzing the effects of ITPR2 and MCU loss on OIS and replicative senescence.

Main Results:

  • Loss of ITPR2 and MCU facilitates escape from oncogene-induced senescence (OIS).
  • During OIS, ITPR2 mediates ER calcium release, followed by MCU-dependent mitochondrial calcium uptake.
  • This ER-mitochondria calcium transport leads to decreased mitochondrial membrane potential, increased reactive oxygen species, and subsequent senescence.
  • The identified ER-mitochondria calcium transport mechanism is also implicated in replicative senescence.

Conclusions:

  • ITPR2 and MCU are identified as novel regulators of cellular senescence.
  • A novel pathway involving ER-mitochondria calcium transport regulates both OIS and replicative senescence.
  • Targeting this calcium transport mechanism may offer new therapeutic strategies for senescence-related diseases.

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