Elsevier

Toxicology Letters

Volume 99, Issue 3, 12 November 1998, Pages 157-168
Toxicology Letters

Biochemical determinants of apoptosis and necrosis

https://doi.org/10.1016/S0378-4274(98)00155-6Get rights and content

Abstract

Although apoptosis and necrosis were originally thought to be entirely distinct mechanisms of cell death, recent work has shown that the processes are regulated by many of the same biochemical intermediates, most notably the levels of cellular ATP, Ca2+, reactive oxygen species, and thiol antioxidants. Beyond a certain threshold, it appears that stress-induced changes in these modulators `switches' the cell death mechanism from apoptosis to necrosis. Importantly, even when this occurs, cell death can be attenuated by bcl-2 and caspase inhibitors, which are known for their abilities to block apoptosis. This review will summarize these observations within the context of what is currently known about the effector machinery for apoptotic cell death, and possible mechanistic explanations for the switch between apoptosis and necrosis will be provided.

Section snippets

Introduction: distinctions between apoptosis and necrosis

The term `apoptosis' was originally coined by Kerr et al. (1972)to describe a pattern of morphological alterations associated with normal programmed cell death and certain pathological processes in vivo. These changes include cell shrinkage and loss of contact with neighboring cells, formation of cytoplasmic vacuoles, plasma and nuclear membrane blebbing, and chromatin condensation, and an important feature was that they could be readily distinguished from those occurring during `accidental'

Molecular regulation of apoptosis: lessons from Caenorhabditis elegans

For years the study of apoptosis relied solely upon somewhat subjective assessments of cellular morphology, which left many scientists understandably sceptical about the pathway's relevance. This skepticism was ameliorated somewhat when endonuclease activation emerged as a biochemical indicator of apoptosis. However, in the absence of any information about the genetic control of the process, investigators remained unconvinced that apoptosis represented a mechanistically unique cell death

Triggers for apoptosis

Numerous extracellular stimuli can initiate apoptosis (Fig. 2). However, it appears that they can be grouped into two general categories based upon their overall mechanisms of action. In the first group are polypeptides homologous to the receptor for tumor necrosis factor (TNF) and CD95/Fas, which are directly coupled to the cell death machinery. Members of this family interact physically with caspases via regions in their cytoplasmic domains known as the `death domains,' and receptor

Mechanisms of caspase activation

Other genetic studies in C. elegans revealed that ced-9 and ced-4 function upstream of ced-3 in the apoptotic pathway, suggesting that caspase activation might be rate-limiting for apoptosis (Hengartner and Horvitz, 1994a). However, precisely how caspase activation is triggered in whole cells remained unclear. Early clues came from Korsmeyer's laboratory, who demonstrated that a substantial fraction of cellular bcl-2 protein localizes to mitochondria (Hockenbery et al., 1990). Subsequent work

Biochemical determinants of apoptosis and necrosis

Even though the morphological alterations associated with each response are (by definition) distinct, accumulating evidence indicates that certain key biochemical mechanisms are shared by the two responses. Early work from Cotter's laboratory using a panel of toxicants demonstrated that low to moderate concentrations trigger apoptosis and higher levels necrosis (Lennon et al., 1991), and more recent work established a similar dose-dependent relationship between apoptosis and necrosis in

Conclusions

As a result of the work outlined above and other studies, a clear-cut distinction between apoptosis and necrosis no longer exists at the biochemical level, because overexpression of BCL-2 can delay cell death in either case. The effects of bcl-2 appear due in part to direct effects on the mitochondria, which lead to stabilization of membrane potential, preservation of ATP production, prevention of oxidative stress and sustained intracellular Ca2+ alterations, and modulation of intracellular GSH

Acknowledgements

Supported by grants from the National Cancer Institute (CA69676) and the National Heart, Lung, and Blood Institute (HL60537).

References (100)

  • J.A. Kazzaz et al.

    Cellular oxygen toxicity. Oxidant injury without apoptosis

    J. Biol. Chem.

    (1996)
  • Y.M. Kim et al.

    Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms

    J. Biol. Chem.

    (1997)
  • P. Li et al.

    Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade

    Cell

    (1997)
  • X. Liu et al.

    Induction of the apoptotic program in cell-free extracts: requirement for dATP and cytochrome c

    Cell

    (1996)
  • R.A. Lockshin

    Programmed cell death. Activation of lysis by a mechanism involving the synthesis of protein

    J. Insect Physiol.

    (1969)
  • Y. Luo et al.

    Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway

    J. Biol. Chem.

    (1998)
  • S.K. Manna et al.

    Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activated protein-1

    J. Biol. Chem.

    (1998)
  • K. McCall et al.

    Facing death in the fly: genetic analysis of apoptosis in Drosophila

    Trends Genet.

    (1997)
  • D.J. McConkey et al.

    Stimulation of endogenous endonuclease activity in hepatocytes exposed to oxidative stress

    Toxicol. Lett.

    (1988)
  • S. Orrenius et al.

    Role of Ca2+ in toxic cell killing

    Trends Pharmacol. Sci.

    (1989)
  • J.G. Pastorino et al.

    The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition

    J. Biol. Chem.

    (1996)
  • C. Richter

    Pro-oxidants and mitochondrial Ca2+: their relationship to apoptosis and oncogenesis

    FEBS Lett.

    (1993)
  • P.A. Sandstrom et al.

    Lipid hydroperoxides induce apoptosis in T cells displaying a HIV-associated glutathione peroxidase deficiency

    J. Biol. Chem.

    (1994)
  • N. Sata et al.

    Menadione induces both necrosis and apoptosis in rat pancreatic acinar AR4-2J cells

    Free Radic. Biol. Med.

    (1997)
  • J. Savill et al.

    Phagocytic recognition of cells undergoing apoptosis

    Immunol. Today

    (1993)
  • J.R. Tata

    Requirement for RNA and protein synthesis for induced regression of the tadpole tail in organ culture

    Dev. Biol.

    (1966)
  • H. Thor et al.

    The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes

    J. Biol. Chem.

    (1982)
  • Y.Y. Tyurina et al.

    Direct evidence for antioxidant effect of BCL-2 in PC12 rat pheochromocytoma cells

    Arch. Biochem. Biophys.

    (1997)
  • J.N. Vanderbilt et al.

    Endogenous nuclease: properties and effects on transcribed genes in chromatin

    J. Biol. Chem.

    (1982)
  • B. Wagenknecht et al.

    Lipoxygenase inhibitors block CD95 ligand-mediated apoptosis of human malignant glioma cells

    FEBS Lett.

    (1997)
  • J. Yuan et al.

    elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1b-converting enzyme

    Cell

    (1993)
  • H. Zou et al.

    Apaf-1, a human protein homologous to C. elegans ced-4, participates in cytochrome c-dependent activation of caspase-3

    Cell

    (1997)
  • K.L. Backway et al.

    Relationships between the mitochondrial permeability transition and oxidative stress during ara-C toxicity

    Cancer Res.

    (1997)
  • A. Baker et al.

    Thioredoxin, a gene found overexpressed in human cancer, inhibits apoptosis in vitro and in vivo

    Cancer Res.

    (1997)
  • H.K. Bojes et al.

    BCL-XL overexpression attenuates glutathione depletion in FL5.12 cells following interleukin-3 withdrawal

    Biochem. J.

    (1997)
  • E. Bonfoco et al.

    Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures

    Proc. Natl. Acad. Sci. USA

    (1995)
  • A.M. Chinnaiyan et al.

    Interaction of ced-4 with ced-3 and ced-9: a molecular framework for cell death

    Science

    (1997)
  • M.V. Clement et al.

    Superoxide anion is a natural inhibitor of Fas-mediated cell death

    EMBO J.

    (1996)
  • G.M. Cohen

    Caspases: the executioners of apoptosis

    Biochem. J.

    (1997)
  • J.J. Cohen et al.

    Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death

    J. Immunol.

    (1984)
  • Z. Dong et al.

    Internucleosomal DNA cleavage triggered by plasma membrane damage during necrotic cell death

    Am. J. Pathol.

    (1997)
  • J.M. Dybukt et al.

    Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINm5F cells. The role of intracellular polyamines

    J. Biol. Chem.

    (1994)
  • Y. Eguchi et al.

    Intracellular ATP levels determine cell death fate by apoptosis or necrosis

    Cancer Res.

    (1997)
  • V.A. Fadok et al.

    Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages

    J. Immunol.

    (1992)
  • A. Fernandez et al.

    Oxygen radical production and thiol depletion are required for Ca2+-mediated endogenous endonuclease activation in apoptotic thymocytes

    J. Immunol.

    (1995)
  • C. Friesen et al.

    Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells

    Nat. Med.

    (1996)
  • M.O. Hengartner et al.

    Caenorhabditis elegans gene ced-9 protects cells from programmed cell death

    Nature

    (1992)
  • L.A. Herzenberg et al.

    Glutathione deficiency is associated with impaired survival in HIV disease

    Proc. Natl. Acad. Sci. USA

    (1997)
  • D.M. Hockenbery et al.

    BCL-2 is an inner mitochondrial membrane protein that blocks programmed cell death

    Nature

    (1990)
  • T. Hirsch et al.

    The apoptosis-necrosis paradox. Apoptogenic proteases activated after the mitochondrial permeability transition determine the mode of cell death

    Oncogene

    (1997)
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