Apoptosis and Autophagy: Decoding Calcium Signals that Mediate Life or Death

Calcium is a versatile and dynamic 2nd messenger that is essential for the survival of all higher organisms. In cells that undergo activation or excitation, calcium is released from the endoplasmic/sarcoplasmic reticulum to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes; for example, apoptosis and autophagy. In the case of apoptosis, endogenous ligands or pharmacological agents induce prolonged cytosolic calcium elevation, which in turn leads to cell death. In contrast, there is now evidence that calcium regulates autophagy by several mechanisms, and these may be important for maintaining cell survival. Here we summarize what is known about how calcium regulates these life and death decisions. We pay particular attention to pathways that have been described in lymphocytes and cardiomyocytes, as these systems provide optimal models for understanding calcium signaling in the context of normal cell physiology.Apoptosis is a process of programmed cell death or suicide that occurs when cells have undergone irreversible stress or damage. It is required to maintain normal cell homeostasis or to eliminate a population of cells that may be harmful to the organism or unnecessary during organ development (Green 2003). For example, it is the primary mechanism by which potentially autoreactive T cells are eliminated from the immune system. There are two conventional apoptosis pathways: the extrinsic pathway, which is typically initiated by death receptors (e.g., Fas) on the plasma membrane and the intrinsic (mitochondrial) pathway, which involves permeabilization of the outer mitochondrial membrane followed by the release of cytochrome c. In this review, we primarily focus our attention on the intrinsic pathway due to the importance of intracellular calcium in the regulation of this process.In brief, cytochrome c release stimulates apoptosis via its interaction with the protein Apaf-1, which in turn activates the initiator caspase-9 and the executioner caspase-3 (Green 2005). Caspases comprise a family of cysteine proteases that are essential for the classically observed cellular and biochemical characteristics of apoptosis, which include (but are not limited to) membrane blebbing, chromatin condensation, and DNA fragmentation. Another class of cysteine proteases, calpains, require calcium for their activation and are important mediators of apoptosis following ER stress. As discussed later in this review, calpains are reported to directly activate caspases, thus promoting apoptotic cell death independent of mitochondrial cytochrome c release. The following sections provide a more detailed explanation of the varied ways in which calcium signals induce cell death and are themselves regulated.