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

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.

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

“…pLNCX2‐mito‐GCaMP2 (Wiel et al, 2014) and pLPCx‐roGFP2‐ORP1 (Le et al, 2015) retroviral vectors were previously described. The lentiviral vector pLV‐RXRA and the corresponding empty vector pLV were purchased from Vectorbuilder.…”

“…Intracellular calcium levels have been shown to increase in various cell types in response to senescence‐inducing stresses (Borodkina et al, 2016; Wiel et al, 2014; Yu, Li, et al, 2013; Yu, Zhang, Zhou, Yao, & Li, 2013) and activation of the calcium‐dependent transcription factor nuclear factor of activated T cells (NFAT) by the calcium/calmodulin/calcineurin pathway is known to regulate senescence (Manda et al, 2016; Wu et al, 2010). However, how calcium signaling is controlled is still only partially understood.…”

“…However, how calcium signaling is controlled is still only partially understood. We recently discovered that the inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum (ER) calcium release channel, critically contributes to the implementation of cellular senescence (Wiel et al, 2014). Whereas ITPR2 activity has been shown to be modulated through protein interaction and post‐translational modification (Vervloessem, Yule, Bultynck, & Parys, 2015), how ITPR2 is regulated at the expression level is unclear.…”

Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape

“…These observations highlight the need to look for OIS regulators in models relevant to carcinoma. 10,11,14,15 To isolate new OIS regulators, we recently performed a loss-offunction genetic screen to identify genes which, when lost, allow p16 INK4A -negative cells to escape OIS. Using this strategy, we have already identified new OIS regulators.…”

Oxygen Sensing and Integrative Stress Signaling in Plants

“…Potential intracellular calcium sources for the cytosolic spike during oxygen deprivation might be the vacuole, the ER, and mitochondria. Although roles for ER and mitochondria in cytosolic calcium release have been described in mammalian cells (Rizzuto et al, 2012;Wiel et al, 2014), it is still unclear to which extent these organelles contribute to calcium signaling under abiotic stresses in plants.…”