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.

Regulation of cell death: the calcium-apoptosis link.

This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke 'accidental' apoptosis.

/pdf/the-mitochondrial-permeability-transition-pore-and-its-role-54jbv6pihx.pdf

The mitochondrial permeability transition pore and its role in cell death.

Background—This review article deals with the role of calcium in ischemic cell death. A calcium-related mechanism was proposed more than two decades ago to explain cell necrosis incurred in cardiac ischemia and muscular dystrophy. In fact, an excitotoxic hypothesis was advanced to explain the acetylcholine-related death of muscle end plates. A similar hypothesis was proposed to explain selective neuronal damage in the brain in ischemia, hypoglycemic coma, and status epilepticus. Summary of Review—The original concepts encompass the hypothesis that cell damage in ischemia-reperfusion is due to enhanced activity of phospholipases and proteases, leading to release of free fatty acids and their breakdown products and to degradation of cytoskeletal proteins. It is equally clear that a coupling exists between influx of calcium into cells and their production of reactive oxygen species, such as ·O2−, H2O2, and ·OH. Recent results have underscored the role of calcium in ischemic cell death. A coupling has been de...

http://www.reboundhealth.com/cms/images/pdf/Article-by-Various-Authors/calcium%20in%20ischemic%20cell%20death%20id%2015175.pdf

Calcium in Ischemic Cell Death

Ca2+-ATPases (pumps) are key actors in the regulation of Ca2+ in eukaryotic cells and are thus essential to the correct functioning of the cell machinery They have high affinity for Ca2+ and can efficiently regulate it down to very low concentration levels Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+ The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca2+-signaling dysfunction Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca2+ homeostasis that are incompatible with cell life However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca2+-controlling and/or processing machinery They do not bring cells to immediate death but seriously compromise their normal functioning

Calcium Pumps in Health and Disease

Calcium and cell death mechanisms: a perspective from the cell death community.

Myocardial fiber necrosis due to intracellular Ca overload-a new principle in cardiac pathophysiology.

Skeletal and heart muscle fibers undergo severe functional and structural alterations, resulting in necrotization as soon as extracellular Ca ions penetrate excessively into the sarcoplasm, so that the capacities of the Ca binding or extrusion processes become insufficient. In mechanically injured skeletal muscle fibers, this necrotization process begins in the neighborhood of the membrane lesion where a large Ca inward transport takes place. Accordingly, elimination of Ca from the Ringer solution or an outward electric current which blocks the influx of extracellular Ca prevents the onset of necrotization, whereas additional Ca or an inward electric current which augments the influx of Ca potentiates the course of degradation. The crucial reaction in the production of necroses in skeletal and heart muscle fibers is a high energy phosphate deficiency which results (a) from excessive activation of Ca-dependent intracellular ATPases, and (b) from Ca-induced mitochondrial destruction. This applies especially to myocardial fiber damage caused by large doses of beta-adrenergic catecholamines such as isoproterenol. The number and size of the isoproterenol-induced cardiac lesions are obviously determined by the extent and, particularly, by the duration of the Ca-mediated high energy phosphate penury. Substances which sensitize the myocardium to catecholamine-induced necrotization (9-alpha-fluorocortisol, dihydrotachysterol, NaH2PO4) act by potentiating intracellular Ca overload and high energy phosphate breakdown. Conversely, verapamil D 600, and other Ca-antagonistic compounds protect the structural integrity of the heart muscle fibers by restricting transmembrane Ca influx and, consequently, ATP and creatine phosphate exhaustion.

Key role of Ca in the production of noncoronarogenic myocardial necroses.

In den letzten 15 Jahren haben in der experimentellen Kardiologie auch solche Nekrose-Formen wachsende Beachtung gefunden, bei denen nicht a priori eine myokardiale Durchblutungsstorung ins Auge springt. An erster Stelle steht hier die experimentelle Nekrose-Erzeugung durch endogene Catecholamin-Ausschuttung in Stres-Situationen oder durch Injektion hoher Dosen von Catecholaminen, speziell von Isoproterenol (Aludrin). Vorbehandlung der Tiere mit bestimmten Corticosterioden, mit AT 10, Vitamin Doderein alimentarer K+-Mangel kann diese Nekrosen enorm verstarken. Durch prophylaktische Gaben von K+- oder Mg++-Salzen konnen die Nekrosen umgekehrt abgeschwacht oder verhutet werden. Selye, Bajusz, Raab, Rona und andere Autoren haben dieses Forschungsgebiet vornehmlich unter morphologischem Aspekt ausfuhrlich dargestellt.

Die intracelluläre Überladung mit Kalzium als entscheidender Kausalfaktor bei der Entstehung nicht-coronarogener Myokard-Nekrosen

The crucial point in the pathogenesis of isoproterenol-induced myocardial necrotization is an abundant intracellular Ca accumulation leading to high energy phosphate exhaustion. Accordingly, in the early stage of the isoproterenol-induced necrotization process, the onset of ATP and creatine phosphate breakdown strictly parallels the acute Ca gain. In this type of necrosis, the Mg losses from the myocardium appear as a concomitant phenomenon. The hearts can be protected against the deleterious Ca overload and necrotization by increasing the plasma concentration of Mg, K, or H ions in order to counterbalance Ca according to the ration (see article). On the other hand, if Mg, K, or H ion concentrations are too low, isoproterenol-induced Ca uptake and myocardial lesions are potentiated.

Prevention of myocardial Ca overload and necrotization by Mg and K salts or acidosis.

Uberdosierung von Vitamin D oder Dihydrotachysterol (DHT) fuhrt insbesondere bei kombinierter Verabreichung mit NaH2PO4 bei Ratten nicht nur zu Myokard-Lasionen, sondern auch zu arteriosklerotischen Gefasprozessen (1). Nach unseren vorausgegangenen Studien mit markiertem 45Ca ist die Nekrotisierung durch eine Ca++-Uberladung der Myokardfasern bedingt und dahernach Schwere und Ausdehnung mit der 45Ca-Inkorporation quantitativ korreliert (2,3). Organische Ca++-Antagonisten wie Verapamil, Substanz D 600 oder Prenylamin, die den transmembranaren Ca++-Influx in die Myokardfasern reduzieren, konnten daher die Nekrosebildung verhuten. Ahnlich wirkten K+- und Mg++-Salze als naturliche Ca++-Antagonisten. Ganz analoge Verhaltnisse wurden nunmehr an den Gefasen gefunden: Ratten wurden 10 Tage lang peroral taglich mit 2 mal 10 mM/kg NaH2PO4 und 7 Tage lang peroral taglich mit 1 mal 0, 5 mg/kg DHT vorbehandelt. Am elften Tag wurde intraperitoneal 45Ca (10 /uC/kg) injiziert und die 45Ca-Inkorporation in Aorta und Arteria mesenterica sup. gemessen. Bei den unbehandelten Kontrollratten erreichte der 45Ca-Gehalt in der Aortenwand innerhalb von 6 Stunden nach der 45Ca-Injektion 70% und in der Mesenterial-Arterie etwa 100% (bezogen auf die Plasma-Aktivitat = 100%), wahrend bei den vorbehandelten Tieren der 45Ca-Gehalt der Aorta innerhalb der gleichen Beobachtungszeit auf 5000–8000%y d.h. auf das 70–120-fache und der Mesenterial-Arterie auf 4000–5000%, d.h. auf das 40-50-fache der Norm anstieg.

Hemmung arteriosklerotischer Gefäßprozesse durch prophylaktische Behandlung mit MgCl2, KCl und organischen Ca++-Antagonisten (Quantitative Studien mit Ca45 bei Ratten)

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