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Selvaraj, S. Calcium Signaling Regulates Autophagy. Encyclopedia. Available online: https://encyclopedia.pub/entry/14835 (accessed on 26 December 2024).
Selvaraj S. Calcium Signaling Regulates Autophagy. Encyclopedia. Available at: https://encyclopedia.pub/entry/14835. Accessed December 26, 2024.
Selvaraj, Senthil. "Calcium Signaling Regulates Autophagy" Encyclopedia, https://encyclopedia.pub/entry/14835 (accessed December 26, 2024).
Selvaraj, S. (2021, October 04). Calcium Signaling Regulates Autophagy. In Encyclopedia. https://encyclopedia.pub/entry/14835
Selvaraj, Senthil. "Calcium Signaling Regulates Autophagy." Encyclopedia. Web. 04 October, 2021.
Calcium Signaling Regulates Autophagy
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This entry is adapted from the peer-reviewed paper 10.3390/cells10082125

Calcium (Ca2+) functions as a second messenger that is critical in regulating fundamental physiological functions such as cell growth/development, cell survival, neuronal development and/or the maintenance of cellular functions. The coordination among various proteins/pumps/Ca2+ channels and Ca2+ storage in various organelles is critical in maintaining cytosolic Ca2+ levels that provide the spatial resolution needed for cellular homeostasis. An important regulatory aspect of Ca2+ homeostasis is a store-operated Ca2+ entry (SOCE) mechanism that is activated by the depletion of Ca2+ from internal ER stores and has gained much attention for influencing functions in both excitable and non-excitable cells.

calcium signaling calcium channels autophagy apoptosis stem cells neuronal and immune cell function

1. Introduction

Calcium is a prominent regulator for diverse processes such as gene transcription, proliferation, cell motility, cell signaling, neuronal regulation, autophagy and apoptosis [1]. To perform such a broad spectrum of functions, the cells have evolved multiple unique mechanisms that are modulated by different proteins that regulate cellular Ca2+ levels. In addition, the spatial and temporal regulation of Ca2+ levels that is maintained by various Ca2+ channels, transporters, pumps, and their binding to key proteins, play an essential role in maintaining a tight control on intracellular Ca2+ levels. The transient receptor potential (TRP) channels have been studied extensively and play a prominent role in regulating various cellular functions [2][3][4]. The TRPC subfamily consists of seven members (TRPC1-7) with diverse modes of regulation and physiological function. Intracellular Ca2+ plays a crucial role in both basal and induced autophagy [5][6]. Plenty of evidence has suggested a complex role of Ca2+ in the regulation of autophagy as well as in the regulation of apoptosis [7]. However, the mechanism by which Ca2+ controls autophagy and apoptosis remains controversial [8]. Previous studies have shown a negative role of Ca2+ in regulating autophagy that induces apoptosis [5][9], while many studies showed a positive role of Ca2+ in activating autophagy [1][8][10][11]. Nonetheless, Ca2+-permeable channels have emerged as important factors in modulating both basal and induced autophagy that can also prevent apoptosis. In mammalian cells, starvation causes autophagosomes to form omegasomes at the endoplasmic reticulum (ER). Autophagy is induced either by mammalian target of rapamycin (mTOR) inactivation, or adenosine monophosphate (AMP) activated protein kinase (AMPK) activation, which causes distinct Unc-51-like autophagy activating kinase 1 (ULK1) activation [12][13][14] (Figure 1A). Altered Ca2+ transmission has been implicated in a variety of processes fundamental for both non-excitable and excitable cells. Here, we review what is known about Ca2+-channel-induced Ca2+ signaling and how this fundamental second messenger regulates life and death decisions, with particular attention directed to cell autophagy in both excitable and non-excitable cells.
Cells 10 02125 g001 550
Figure 1. Ca2+ signaling and its function in cell survival. Model showing the common Ca2+ signaling pathways is shown in (A). Cells have several mechanisms for regulating cytosolic Ca2+ concentration. The activation of G coupled protein receptor (GPCR or receptor tyrosine kinase (RTK) complex activates PLC, which catalyzes the dissociation of PIP2 to form diacylglycerol and IP3. IP3 binds to its receptors in the ER (IP3R), resulting in the release of the stored Ca2+ from the ER. Emptying of the ER Ca2+ activates the STIM protein to translocate to the PM and binds to Ca2+ channels (TRPCs/Orais). Activation of these Ca2+ channels or regulation of other Ca2+ channels (TRPs and voltage-gated channels) increases cytosolic calcium levels that maintain autophagy and inhibits apoptosis. (B) A summary of the pathways that are activated upon an increase in cytosolic calcium levels is shown in the schematic diagram.

2. Autophagy and Apoptosis Crosstalk Is Guided by Ca2+ Influx

Intracellular Ca2+ plays a crucial role in both basal and induced autophagy along with modulating apoptosis [5][6] (Figure 1A,B). Autophagy, or “self-eating”, is a highly conserved and dynamic catabolic process termed as a fundamental cell survival system, intracellular clearance pathway and major intracellular degradation mechanism. Cellular stress, including damaged mitochondria, protein aggregation, bacterial and viral infections, tumors, hypoxia, aging and metabolic stress, activate the cellular autophagy pathway in the cells, resulting in a modified, surplus, or harmful intracellular components being sequestered in autophagosomes and surrendered to the lysosome for the degradation and recycling of intracellular components to regenerate the macromolecule and produce energy during the dynamic program of stem cell proliferation, self-renewal and differentiation [8][15].
Apoptosis is a genetically controlled and evolutionarily conserved form of cell death that is important for normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. Programmed cell death or apoptosis is a genetically determined cell routine in which cells undergo an unexpected decline in homeostasis and functionality, triggering several intracellular pathways and ultimately cell death. The role of Ca2+ as a death trigger has been long proposed, and it has been shown that the entry of excess Ca2+ into cells might be the mechanism underlying the tissue pathology [1][6]. Ca2+ release from the ER, as well as Ca2+ entry that is taken up by the mitochondria, is pivotal in triggering apoptotic signals and is one of the mechanisms through which the overexpression of antiapoptotic proteins (or ablation of proapoptotic ones) counteracts cell death. The amount of releasable Ca2+—rather than the Ca2+ concentration of the ER—seems to be the relevant parameter for the transduction of the death signal, as it controls the ‘amplitude’ of the signal reaching the mitochondria [1][5][8][16][17][18].

3. Calcium as Regulator for Apoptosis

Apoptosis is a well-characterized mechanism of programmed cell death and is functionally distinct from autophagy. Notably, in many cell types and disease conditions, the activation of autophagy inhibits the apoptotic mediated cell death, whereas autophagy inhibition activates the apoptotic process [19][20]. However, in some physiological conditions, the proteins originally involved in regulating autophagy might also induce apoptosis [19]. Interestingly, many stimuli that ultimately cause apoptosis also trigger autophagy in the same cell, where autophagy occurs first, and if not resolved, it may proceed to apoptosis [21][22][23]. Apoptosis can be triggered by various cellular signals, especially the intracellular Ca2+. Several studies have provided strong experimental evidence that supports the involvement of intracellular Ca2+ homeostasis in the induction of apoptosis [24][25][26]. Fleckenstein et al. provided the first evidence that showed the intracellular Ca2+ overload caused by excessive Ca2+ influx induces cell death in myocytes [27]. Similarly, the lethal effect of intracellular Ca2+ overload in cell survival was scrutinized using Ca2+ ionophore/chelator in thymocytes. Notably, Ca2+ ionophore A23187 mimics the apoptotic effect of glucocorticoid, and the removal of extracellular Ca2+ by EGTA diminishes the cytolytic action of glucocorticoid and A23187, suggesting that Ca2+ influx and intracellular Ca2+ concentration play a crucial role in cell survival/apoptosis [28]. Several other studies have shown that exposing the cells to different apoptotic inducers causes a sustained increase in intracellular Ca2+ concentration, which in turn activates the endonuclease and initiates the programed cell death cascade [29][30][31]. The increase in intracellular Ca2+ concentration in cells is mainly achieved either by increased Ca2+ influx through the plasma membrane Ca2+ channels or Ca2+ release from the internal storage such as the endoplasmic reticulum (ER) and mitochondria. In addition to intracellular Ca2+ overload, other studies have shown that apoptosis can be triggered by both Ca2+ depletion from the ER and Ca2+ entry through the plasma membrane [32].

4. Intracellular Ca2+ Stores in Regulating Apoptotic Function

The ER is a major Ca2+ storage organelle in mammalian cells, which maintain a concentration of around 1mM compared with 100 nM in the cytosol and mitochondria. Ca2+ homeostasis in the ER is essential for the activity of molecular chaperones and the folding of enzymes. Dysregulation in ER Ca2+ content affects protein folding, leading to the accumulation of misfolded proteins in the ER and inducing ER stress. Cells activate defense mechanisms such as the unfolded protein response (UPR) to remove the unfolded and/or incorrectly folded accumulated proteins in the ER [33][34]. Therefore, mild or transient ER stress activates several pathways to combat the ER stress, including the activation of chaperones, folding enzymes, reactive oxygen species (ROS) scavengers, and degradative pathways, such as autophagy. In contrast, these pathways can also induce apoptosis when the cells experience severe or prolonged ER stress [35][36].
ER Ca2+ homeostasis is tightly regulated by active Ca2+ uptake via Ca2+ pumps from the cytosol and Ca2+ release from the ER by Ca2+ leak channels. The Ca2+ release from the ER occurs primarily via inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) or ryanodine receptors (RyRs); however, other Ca2+ leak channels also exist in the ER, and these channels are restricted to excitable cell types [37][38]. IP3R is predominantly localized on the ER, is one of the major ER Ca2+ leak channels, and IP3R-mediated Ca2+ release induces the release of several pro-apoptotic factors from the mitochondria and activates apoptosis. IP3R1-deficient T cells showed resistance to apoptosis induced by dexamethasone, T cell receptor (TCR) stimulation, ionizing radiation, and Fas stimulation [39]. Interestingly, increasing the intracellular Ca2+ concentration by thapsigargin makes the IP3R1-deficient T cells susceptible to TCR-mediated apoptosis. Interestingly, the removal of external Ca2+ has no effect on the TCR-mediated apoptosis in thapsigargin-treated cells, suggesting that ER store depletion is sufficient and Ca2+ entry is not required to trigger TCR-mediated apoptosis [39]. In another study, the expression of IP3R was upregulated in lymphocytes exposed with apoptotic inducers, and the augmented receptor population was localized to the plasma membrane. Notably, the antisense-mediated silencing of type 3 IP3R (IP3R3), but not type 1 IP3R, inhibited dexamethasone-induced apoptosis in the mouse S49 T-lymphoma cell line, suggesting that Ca2+ release via IP3R3 is required to trigger autophagy that inhibited apoptosis [29].
Ca2+ release from the ER transmits Ca2+ to the surrounding mitochondria via the mitochondria-associated ER membranes (MAMs). The stimulation of IP3R releases Ca2+ from the ER, which generates high-Ca2+ microdomains at the ER–mitochondrial junction, leading to the activation of mitochondrial Ca2+ uniporter and subsequent mitochondrial Ca2+ uptake. Ca2+ homeostasis in the mitochondria is required in regulating the activity of Krebs cycle enzymes and transporters, impacting its bioenergetic and biosynthetic function [40][41][42]. Various apoptotic stimuli cause the release of excessive Ca2+ from the ER and subsequent Ca2+ overload into the mitochondria, resulting in the constant opening of the mitochondrial permeability transition pore (PTP), that leads to mitochondrial swelling with perturbation or rupture of the outer mitochondrial membrane (OMM) and alters the mitochondrial membrane potential [43][44][45]. The rupture of OMM activates the release of several pro-apoptotic proteins such as cytochrome c, apoptosis-inducing factor (AIF), procaspase 9, Smac/DIABLO, and endonuclease G into the cytosol, where it partners with other proteins and initiates the signaling cascade, leading to apoptosis [35][46][47][48][49]. The critical role of Ca2+ and apoptosis was further reinforced while studying the mechanism of action of the anti-apoptotic proteins, such as B cell lymphoma 2 (Bcl-2), B cell lymphoma extra-large (Bcl-XL) and myeloid cell leukemia 1 (Mcl-1). Bcl-2 is a critical regulator in controlling apoptotic cell death by neutralizing proapoptotic Bcl-2 family members at the mitochondria. Bcl2 also regulates Ca2+ homeostasis in the ER and mitochondria and controls the cell death pathway [50]. Interestingly, Bcl-2 overexpression has been shown to inhibit cell death by decreasing the steady-state Ca2+ levels in the ER, thereby reducing Ca2+ transfer from the ER to the mitochondria [51]. On the other hand, proapoptotic BAX promotes cell death by increasing the Ca2+ mobilization from the ER to the mitochondria. Moreover, the loss of BAX reduced resting ER Ca2+ levels that resulted in diminished mitochondrial Ca2+ uptake and were highly resistant to apoptosis [52].

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