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  • Review Article
  • Published:

Calcium

Regulation of cell death: the calcium–apoptosis link

Nature Reviews Molecular Cell Biology volume 4, pages 552–565 (2003)Cite this article

Key Points

  • Ca2+ has long been known to be potentially cytotoxic, and cellular Ca2+ overload was first linked to necrotic cell death in the heart and liver.

  • Subsequent studies also revealed a central role for Ca2+ in apoptosis signalling. This was first shown in thymocytes and lymphocytes and, in some studies, was thought to involve activation of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. Other studies indicated that depletion of the ER Ca2+ pool might, in fact, be more important for the pro-apoptotic effect than an increase in the cytosolic Ca2+ concentration.

  • The importance of ER–mitochondrial Ca2+ fluxes and the central function of mitochondria in the Ca2+-regulated cell death programme are now well established, and Ca2+-mediated mitochondrial permeability transition is recognized as an important mechanism for cytochrome c release and caspase activation in apoptosis.

  • Recent findings have provided ample evidence for crosstalk between calpains, caspases and other protease families and have indicated new pathways that lead directly from a Ca2+ signal to caspase activation and apoptosis.

  • The discoveries that intracellular Ca2+ compartmentalization and ER–mitochondrial Ca2+ fluxes are modulated by Bcl-2 family proteins, and that caspase cleavage of Ca2+ transporters might cause perturbation of intracellular Ca2+ homeostasis and thereby both aggravate the damage and affect the mode of cell death, provides further support for the Ca2+–apoptosis link.

  • Finally, Ca2+-regulated processes are also involved in signalling for clearance of apoptotic cells and cell debris by phagocytes. So, the termination of the apoptotic death process is also part of the Ca2+–apoptosis link.

  • The potential importance of the Ca2+–apoptosis link in disease pathogenesis is now evident but needs to be substantiated further. Similarly, although we have already entered the era of developing new pharmaceuticals that target apoptosis, both the beneficial and the potential adverse effects of such therapy must be critically evaluated.

Abstract

To live or to die? This crucial question eloquently reflects the dual role of Ca2+ in living organisms – survival factor or ruthless killer. It has long been known that Ca2+ signals govern a host of vital cell functions and so are necessary for cell survival. However, more recently it has become clear that cellular Ca2+ overload, or perturbation of intracellular Ca2+ compartmentalization, can cause cytotoxicity and trigger either apoptotic or necrotic cell death.

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Figure 1: The regulation of intracellular Ca2+ compartmentalization.
Figure 2: ER stress: causes and consequences.
Figure 3: Mechanisms of release of intermembrane-space proteins from mitochondria.
Figure 4: Crosstalk between calpains and caspases during apoptosis.
Figure 5: Positive and negative recognition signals for phagocytosis of apoptotic cells.

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Acknowledgements

Work in the authors' laboratories was supported by grants from the Swedish and the UK Medical Research Councils, the Swedish Cancer Society and the European Commission. The authors thank S. J. Korsmeyer and S. H. Snyder for sharing unpublished data.

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Authors and Affiliations

  1. Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden

    Sten Orrenius & Boris Zhivotovsky

  2. MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester, LEI 9HN, UK

    Pierluigi Nicotera

Authors
  1. Sten Orrenius
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  2. Boris Zhivotovsky
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  3. Pierluigi Nicotera
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Corresponding author

Correspondence to Sten Orrenius.

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DATABASES

LocusLink

Bax

Ins(1,4,5)P3 receptor

Swiss-Prot

Bad

Bak

BAP31

Bcl-2

Bcl-XL

BiP

calmodulin

CD31

CED-3

CED-4

CED-9

granzyme A

Ire1α

m-calpain

t-Bid

TRAF-2

FURTHER INFORMATION

Institute of Environmental Medicine

MRC Toxicology Unit

Glossary

PROGRAMMED CELL DEATH

A genetically controlled form of cell death that is important for normal development.

APOPTOSIS

A morphologically defined mode of cell death that is characterized by cell shrinkage, plasma-membrane blebbing and nuclear condensation and fragmentation.

ISCHAEMIA

A condition in which oxygen deprivation of the tissue is accompanied by inadequate removal of metabolites because of reduced blood flow or perfusion.

CASPASE

A cysteine-dependent aspartate-specific protease that is activated during apoptotic cell death or inflammation.

BCL-2 FAMILY

A family of proteins that either promote or inhibit cell death.

NECROSIS

A mode of cell death that is characterized by cell swelling, rupture and inflammation of the surrounding tissue.

BLEBBING

The formation of blebs, or protrusions, of the plasma membrane.

AUTOPHAGIC CELL DEATH

A degradative pathway that terminates in the lysosomal compartment after the formation of a cytoplasmic vacuole that engulfs macromolecules and organelles.

CALMODULIN

A calcium-binding protein that has a role in Ca2+ signalling.

DEATH-INDUCIBLE SIGNALLING COMPLEX

A protein complex formed at the plasma membrane after death-receptor ligation, which is involved in apoptosis signalling.

APOPTOSOME

The complex that is formed by Apaf-1, cytochrome c and pro-caspase-9, in the presence of dATP, which results in caspase activation and apoptosis.

GRANZYME A

A serine protease that mediates caspase-independent cell death.

NM23-H1

A nucleoside diphosphate kinase that is implicated in the suppression of tumour metastasis.

INOSITOL-1,4,5-TRISPHOSPHATE RECEPTOR

A receptor that is localized mainly in the endoplasmic reticulum. It mediates the release of Ca2+ into the cytosol.

CALPAIN

A family of Ca2+-activated cysteine proteases that have a role in cell death.

SARCO(ENDO)PLASMIC RETICULUM CA2+-ATPASE

(SERCA). A pump located in the sarcoplasmic or endoplasmic reticulum membranes that couples ATP hydrolysis to the transport of Ca2+ from cytosolic to lumenal spaces.

BH3-ONLY FAMILY

Pro-apoptotic Bcl-2 proteins that contain the BH3 domain, but lack the BH1, BH2 and BH4 domains.

CYTOCHROME C

A haem-containing protein that functions as an electron carrier in the mitochondrial respiratory chain and as a cofactor for caspase activation during apoptosis.

CALCINEURIN

A Ca2+/calmodulin-activated protein phosphatase that is involved in Ca2+ signalling.

VOLTAGE-DEPENDENT ANION CHANNEL

A pore in the outer membrane of the mitochondria that mediates transport of anions and certain other small molecules in and out of the mitochondria.

ADENINE NUCLEOTIDE TRANSLOCATOR

A carrier that is located in the inner mitochondrial membrane and that transports ADP into, and ATP out of, the mitochondrial matrix.

CARDIOLIPIN

An anionic phospholipid that is uniquely localized in the inner mitochondrial membrane and that is of vital importance for the function of the respiratory chain and the adenine nucleotide translocator.

NITRIC OXIDE SYNTHASE

(NOS). A Ca2+-activated enzyme in endothelial cells (eNOS) or neurons (nNOS) that forms nitric oxide from the amino acid, L-arginine. Another isoform, inducible (i)NOS, can be expressed in various cell types but is independent of calcium.

PHOSPHOLIPASE A2

A Ca2+-dependent enzyme that releases arachidonic acid from phospholipids in cellular membranes.

TISSUE TRANSGLUTAMINASE

A Ca2+-dependent enzyme that is involved in the crosslinking of proteins in apoptotic cells.

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Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: the calcium–apoptosis link. Nat Rev Mol Cell Biol 4, 552–565 (2003). https://doi.org/10.1038/nrm1150

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