Ion homeostasis and apoptosis

doi:10.1016/S0955-0674(00)00228-3

Current Opinion in Cell Biology

Volume 13, Issue 4, 1 August 2001, Pages 405-411

https://doi.org/10.1016/S0955-0674(00)00228-3 Get rights and content

Abstract

Alterations in the transmembrane gradients of several physiological ions may influence programmed cell death. In particular, recent data suggest that increases in intracellular calcium may either promote or inhibit apoptosis, depending on the level, timing and location, whereas loss of intracellular potassium promotes apoptosis.

Introduction

Programmed cell death leading to apoptosis is essential for normal tissue development and homeostasis, and it contributes to certain forms of pathological cell loss. Although apoptosis was originally defined by characteristic morphological features, including cell body shrinkage, nuclear condensation, chromatin margination and the formation of membrane-bound cellular remnants (apoptotic bodies), it is now better defined by its macromolecular underpinnings. Bcl-2 family proteins, including bax, bid and bcl-xL, typically regulate the release of cytochrome c and other apoptogenic factors from mitochondria; cytochrome c interacts with Apaf-1 and caspase-9 to form an ‘apoptosome’ capable of activating effector caspases such as caspase-3. Caspases can also be activated by cell surface ‘death receptors’ such as tumor necrosis factor (TNF) receptors via caspase-8 [1•].

Evidence is also emerging for a caspase-independent pathway of mammalian cell apoptosis, mediated by the mitochondrial release of apoptosis-inducing factor (AIF) [2••]. In comparison, less is understood about the accompanying changes in intracellular ionic homeostasis, although apoptotic cell shrinkage must indicate a substantial movement of water and ions across the plasma membrane. Such a shift is also central to the major alternative form of cell death, necrosis.

This brief review will discuss evidence suggesting that changes in intracellular ion homeostasis mediate or modify apoptosis. It will also focus on changes in intracellular free calcium ([Ca²⁺]_i) and potassium ([K⁺]_i).

Section snippets

Multiple roles for cellular calcium in apoptosis

Cellular Ca²⁺ overload has been suggested to be the final common pathway of cell death 3., 4.. In recent years, as distinctions between necrosis and apoptosis have become better appreciated, elevated [Ca²⁺]_i has retained its status as a key factor in necrosis [5], whereas a more variegated relationship has emerged between [Ca²⁺]_i and apoptosis. As extracellular Ca²⁺ concentrations ([Ca²⁺]_e) typically exceed [Ca²⁺]_i by four orders of magnitude, a large increase in Ca²⁺ influx and [Ca²⁺]_i

Potassium efflux and apoptosis

As K⁺ is the predominant intracellular cation (typically present at around 140 mM), it is plausible that apoptotic cell shrinkage would be accompanied by loss of cellular K⁺ (Fig. 3). Barbiero et al. [47] used the K⁺-sensitive fluorescent dye PBFI to estimate that the [K⁺]_i in apoptotic mouse L fibroblast cells falls below 50 mM. This would also suggest that K⁺ efflux exceeded water efflux. Measurements performed on CEM-C7A lymphoma cells during dexamethasone-induced apoptosis also confirmed

Chloride channels, volume control and apoptosis

Two events closely associated with intracellular K⁺ and Cl⁻ efflux and water efflux/cell shrinkage have also been implicated in the regulation of apoptosis, although it is presently unclear to what extent the influence of these is mediated independently, rather than through secondary effects on K⁺ efflux and [K⁺]_i ([81]; Fig. 3). An outwardly rectifying Cl⁻ channel is activated in Jurkat T lymphocytes by apoptotic signals [82], and elevating extracellular Cl⁻ or adding pharmacological Cl⁻

Other ions

A role for excess Mg²⁺ entry and toxic elevations of intracellular Mg²⁺ levels in glutamate-induced neuronal death has been proposed [85]. The toxic translocation of endogenous Zn²⁺ from presynaptic nerve terminals into the cytosol of postsynaptic target neurons has been implicated in the pathogenesis of selective neuronal death after global ischemia 86., 87., which is probably, at least in part, apoptotic [11]. The surprising finding of elevated Zn²⁺ levels in neurons dying after sustained

Conclusions

Alterations in the cellular homeostasis of several physiological ions appear to be important modifiers or mediators of the apoptotic cascade. Although Ca²⁺ or K⁺ have figured most prominently in studies to date, pro-apoptotic effects of Cl⁻ and water efflux have been proposed, and other ions may participate in certain circumstances. Further examination of the relationship between ionic homeostasis and apoptosis is warranted and may aid identification of strategies for the therapeutic

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

•of special interest
••of outstanding interest

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ReviewIon homeostasis and apoptosis

Abstract

Introduction

Section snippets

Multiple roles for cellular calcium in apoptosis

Potassium efflux and apoptosis

Chloride channels, volume control and apoptosis

Other ions

Conclusions

References and recommended reading

Cell Calcium

Trends Neurosci

Neuron

Prog Neurobiol

Cell Calcium

J Biol Chem

Toxicol Appl Pharmacol

J Biol Chem

J Biol Chem

J Struct Biol

Induction of a caspase-3-like activity by calcium in normal cytosolic extracts triggers nuclear apoptosis in a cell-free system. J Biol Chem

Brain Res

Exp Cell Res

J Biol Chem

Cell Calcium

Semin Cell Dev Biol

J Biol Chem

J Biol Chem

Exp Neurol

Neurosci Lett

Biochem Biophys Res Commun

Exp Cell Res

Exp Cell Res

J Biol Chem

J Biol Chem

Virology

J Biol Chem

Cancer Lett

J Biol Chem

Apoptosis signaling

Annu Rev Biochem

Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death

Nature

Calcium dependence of toxic cell death: a final common pathway

Science

Agonist-induced myopathy at the neuromuscular junction is mediated by calcium

J Cell Biol

Ionized intracellular calcium concentration predicts excitotoxic neuronal death: observations with low-affinity fluorescent calcium indicators

J Neurosci

Gases as biological messengers: nitric oxide and carbon monoxide in the brain

J Neurosci

Calcium regulation of apoptosis

Adv Sec Mess Phosph Res

Programmed death of nonproliferating androgen-independent prostatic cancer cells

Cancer Res

Basic fibroblast growth factor inhibits apoptosis of spontaneously immortalized granulosa cells by regulating intracellular free calcium levels through a protein kinase Cdelta-dependent pathway

Endocrinology

Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells

J Neurosci Res

Activity-dependent regulation of [Ca2+]i in avian cochlear nucleus neurons: roles of protein kinases A and C and relation to cell death

J Neurophysiol

Programmed cell death and the control of cell survival: lessons from the nervous system

Science

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

Maintenance of calcium homeostasis in the endoplasmic reticulum by Bcl-2

J Cell Biol

Blebbing, free Ca2+ and mitochondrial membrane potential preceding cell death in hepatocytes

Nature

Reduced voltage-dependent Ca2+ signaling in CA1 neurons after brief ischemia in gerbils

J Neurophysiol

Review
Ion homeostasis and apoptosis

Activity-dependent regulation of [Ca²⁺]_i in avian cochlear nucleus neurons: roles of protein kinases A and C and relation to cell death

Blebbing, free Ca²⁺ and mitochondrial membrane potential preceding cell death in hepatocytes

Reduced voltage-dependent Ca²⁺ signaling in CA1 neurons after brief ischemia in gerbils