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-x_L, 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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