Calcium alterations signal either to senescence or to autophagy induction in stem cells upon oxidative stress

Abstract

Intracellular calcium ([Ca2+]i) has been reported to play an important role in autophagy, apoptosis and necrosis, however, a little is known about its impact in senescence. Here we investigated [Ca2+]i contribution to oxidative stress-induced senescence of human endometrium-derived stem cells (hMESCs). In hMESCs sublethal H2O2-treatment resulted in a rapid calcium release from intracellular stores mediated by the activation of PLC/IP3/IP3R pathway. Notably, further senescence development was accompanied by persistently elevated [Ca2+]i levels. In H2O2-treated hMESCs, [Ca2+]i chelation by BAPTA-AM (BAPTA) was sufficient to prevent the expansion of the senescence phenotype, to decrease endogenous reactive oxygen species levels, to avoid G0/G1 cell cycle arrest, and finally to retain proliferation. Particularly, loading with BAPTA attenuated phosphorylation of the main DNA damage response members, including ATM, 53BP1 and H2A.X and reduced activation of the p53/p21/Rb pathway in H2O2-stimulated cells. Next, we revealed that BAPTA induced an early onset of AMPK-dependent autophagy in H2O2-treated cells as confirmed by both the phosphorylation status of AMPK/mTORC1 pathway and the dynamics of the LC3 lipidization. Summarizing the obtained data we can assume that calcium chelation is able to trigger short-term autophagy and to prevent the premature senescence of hMESCs under oxidative stress.

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

“…Plasma membrane depolarization has been shown to increase intracellular calcium (Courtney, Lambert & Nicholls, 1990), and increased calcium can promote cell death and senescence (Borodkina et al., 2016; Roderick & Cook, 2008; Wiel et al., 2014; Martin & Bernard, 2017). We also observed increased calcium after plasma membrane depolarization in HEC‐T cells (Figure 6a).…”

Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy

“…However, in some conditions, excessive autophagy caused by stress may exceed the cell-bearing capacity and lead to inflammation, apoptosis, and cell death. Although autophagy has recently been demonstrated to play an important role on the regulation of inflammation, the role of autophagy in the process of lung inflammation has been controversial [32-34]. A decrease in the autophagosome has been shown to induce inflammatory responses and the rescue of autophagy may be used as a novel anti-inflammatory target [35].…”

Crosstalk of ER stress‐mediated autophagy and ER‐phagy: Involvement of UPR and the core autophagy machinery

“…The escalation of intracellular Ca 2+ release into the cytoplasm under ER stress condition, which also involves the activation of autophagy. Ca 2+ release from ER lumen through the IP3R activates a CamKK/AMPK‐dependent pathway that relieves mTOR inhibition on the ULK1 complex, which plays an important role on the induction of autophagy (Borodkina et al, ; Høyer‐Hansen et al, ). Death‐associated protein kinase (DAPK) activation by calcium release participates in Beclin‐1 phosphorylation and subsequent promotes Beclin‐1 dissociation from Bcl‐2, and thus induces autophagy (Simon et al, ; Zalckvar, Berissi, Eisenstein, & Kimchi, ).…”

“…The escalation of intracellular Ca 2+ release into the cytoplasm under ER stress condition, which also involves the activation of autophagy. Ca 2+ release from ER lumen through the IP3R activates a CamKK/AMPK-dependent pathway that relieves mTOR inhibition on the ULK1 complex, which plays an important role on the induction of autophagy (Borodkina et al, 2016;Høyer-Hansen et al, 2007).…”