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Calcium signaling in apoptosis

A description of the role calcium plays in apoptosis, focusing on the endoplasmic reticulum and mitochondria.

Apoptosis is a highly regulated mechanism of cell death, essential in development and tissue homeostasis. Apoptosis can occur via the extrinsic pathway, with ligand binding to death receptors on the cell surface, or via an internal pathway involving the mitochondria.

Learn more about apoptosis pathways

Both pathways converge at the activation of caspases, which cleave cytoskeletal proteins and nuclear lamins, and promote DNA degradation.

It is clear that subtle changes in Ca2+ concentration can regulate and trigger apoptosis. Here we describe how Ca2+ is important in the intrinsic apoptosis pathway by promoting the release of pro-apoptotic factors from mitochondria and subsequent caspase activation.

Ca2+ movement between the endoplasmic reticulum (ER) and mitochondria

The ER is an important Ca2+ storage organelle, maintaining a concentration of 0.1–1 mM, compared with 100 nM in the cytosol and mitochondrial matrix (Hajnóczky et al., 2003). Release of this stored Ca2+ and subsequent uptake by the mitochondria is a mechanism that can trigger apoptosis.

Inositol trisphosphate (IP3) receptor-mediated Ca2+ release from the ER, transmits Ca2+ to surrounding mitochondria using local interactions between ER and mitochondria. This release can be triggered by ER stress when the capacity of the ER to fold proteins properly is compromised (Orrenius et al., 2003).

Alternatively, in a positive feedback mechanism proposed by Boehning et al. (2003), a small amount of cytochrome c is released from mitochondria upon an apoptotic stimulus, which subsequently binds IP3 receptors on the surface or ER, triggering calcium release.

Ca2+ accumulation in the mitochondria leads to mitochondrial membrane permeabilization by stimulating the opening of the mitochondrial permeability transition pore (mPTP, Orrenius et al., 2003). Opening of the mPTP results in the release of pro-apoptotic factors, in particular cytochrome c.

The role of BCL-2 proteins in Ca2+-mediated apoptosis

The BCL-2 family of proteins is central to the regulation of apoptosis. They can be divided into those that are anti-apoptotic such as BCL-2 and BCL-xL, and those that are pro-apoptotic such as BAX, BAK and BAD, among many others.

BCL-2 proteins are associated with mitochondria, where they are involved in altering membrane permeability and regulating the release of cytochrome c and other pro-apoptotic factors (Chipuk et al., 2010). However, they are also associated with the ER, where there is evidence that they have a role in regulating Ca2+ fluxes across the membrane.

Expression of the anti-apoptotic BCL-2 protein reduces Ca2+ release from the ER and subsequent uptake by the mitochondria, either by lowering ER Ca2+ load (Pinton et al., 2000; Foyouzi et al., 2000), or by interacting with IP3 receptor directly, reducing the probability of the channel opening (Rong et al., 2008).

Pro-apoptotic members of the BCL-2 protein family have also been implicated in Ca2+-dependent apoptosis. BAX and BAK control Ca2+ homeostasis in the ER and mitochondria and promote mitochondrial calcium uptake (Scorrano et al., 2003; Nutt et al., 2002). Additionally, BAD and tBID have been shown to sensitize the mitochondria to Ca2+ making them more susceptible to Ca2+ release from the ER (Roy et al., 2009; Csordás et al., 2002).


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References

  • Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010). The BCL-2 family reunion. Mol Cell 37, 299–310.
  • Csordás G1, Madesh M, Antonsson B, Hajnóczky G (2003). tcBid promotes Ca(2+) signal propagation to the mitochondria: control of Ca(2+) permeation through the outer mitochondrial membrane. EMBO J 21, 2198–206.
  • Foyouzi-Youssefi R, Arnaudeau S, Borner C, Kelley WL, Tschopp J, Lew DP, Demaurex N, Krause KH (2000). Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc Natl Acad Sci USA 97, 5723–5728.
  • Hajnόczky G, Davies E, Madesh M (2003). Calcium signaling and apoptosis. Biochem Biophys Res Commun 304, 445–454.
  • Orrenius S, Zhivotovsky B, Nicotera P (2003). Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4, 552–565.
  • Pinton P, Ferrari D, Magalhaes P, Schulze-Osthoff K, Di Virgilio F, Pozzan T, Rizzuto R (2000). Reduced loading of intracellular Ca(2+) stores and downregulation of capacitative Ca(2+) influx in Bcl-2-overexpressing cells. J Cell Biol 148, 857–862.
  • Rong YP, Aromolaran AS, Bultynck G, Zhong F, Li X, McColl K, Matsuyama S, Herlitze S, Roderick HL, Bootman MD, Mignery GA, Parys JB, De Smedt H, Distelhorst CW (2008). Targeting Bcl-2–IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals. Mol Cell 31, 255–265.
  • Roy SS, Madesh M, Davies E, Antonsson B, Danial N, Hajnóczky G (2009). Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+-dependent cell survival and death. Mol Cell 33, 377–388
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