Cyclosporin a protects hepatocytes against prooxidant-induced cell killing

Kass, George E.N.; Juedes, Marlene J.; Orrenius, Sten

doi:10.1016/0006-2952(92)90102-o

Cited by 95 publications

(20 citation statements)

References 45 publications

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“…Cyclosporin A, a potent inhibitor of the pro-oxidant-induced Ca*' release in isolated mitochondria [6,7], blocks mitochondrial Ca*+ release and therefore excessive Ca2+ cycling also in hepatocytes. Cyclosporin A thereby prevents loss of ATP, and keeps the hepatocytes viable [8]. Similar results were reported in [55].…”

Section: The Role Of Mitochondrialsupporting

confidence: 80%

“…Pro-oxidants like tert-butyl hydroperoxide, cumene hydroperoxide, or 3,5-dimethyl-N-acetyl-p-benzoqui- none imine deplete hepatocytes of ATP and kill them [8]. Cyclosporin A, a potent inhibitor of the pro-oxidant-induced Ca*' release in isolated mitochondria [6,7], blocks mitochondrial Ca*+ release and therefore excessive Ca2+ cycling also in hepatocytes.…”

Section: The Role Of Mitochondrialmentioning

confidence: 99%

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

1993

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Apoptosis is a physiological process for active cell removal. One of its hallmarks is an increased cytosolic Ca2+ content. Several genes involved in apoptosis control have been identified, but their mode of action is not understood in detail. Apoptosis may relate to oncogenesis, in that some malignant tumors may grow because genes engaged in apoptosis control are altered. L929 cells overexpressing the proto‐oncogen bcl‐2 have an increased mitochondrial membrane potential (δψ), as have many carcinoma cells, bcl‐2 protects L929 cells against apoptosis caused by pro‐oxidant‐induced mitochondrial Ca2+ ‘cycling’ and increased cytosolic Ca2+ levels. Nerve growth factor, which induces catalase, and inhibitors of mitochondrial Ca2+ release also prevent apoptosis. It is suggested that a pro‐oxidant‐induced Ca2+ release from mitochondria, followed by Ca2+ cycling and ATP depletion, is a common basic event during apoptosis. Accordingly, maintenance of δψ stabilizes mitochondria, thereby prevents apoptosis, and may confer increased growth potential to cells.

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Section: The Role Of Mitochondrialsupporting

confidence: 80%

Section: The Role Of Mitochondrialmentioning

confidence: 99%

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

1993

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“…However, when the Ca 2+ release pathway is stimulated by prooxidants, 'cycling' may become excessive and lead to loss of A N , general leakiness of the inner mitochondrial membrane, inhibition of ATP synthesis, mitochondrial damage, and cell death (reviewed in [27]). Accordant with this concept cyclosporine A (CSA), an inhibitor of prooxidant-induced Ca 2+ release from mitochondria [28], protects against loss of cell viability induced by prooxidants [29] or by NO" [30], and favourably alters liver mitochondrial functions in the postischemic phase at the organ level [31].…”

Section: Mitochondrial Ca 2÷ In Cell Deathmentioning

confidence: 97%

Control of apoptosis by the cellular ATP level

et al. 1996

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Apoptosis is a physiological form of cell death. Its causes and execution mechanisms are not clearly understood. Oxidative stress, nitric oxide and its congeners, Ca 2+, proteases, nucleases, and mitochondria are considered mediators of apoptosis. At present their importance and exact role are elusive but it is clear that mitochondria are both the target and the source of oxidative stress, nitric oxide, and Ca 2÷. The mitochondrial membrane potential (A~b), which is the driving force for mitochondrial ATP synthesis, declines during apoptosis, and maintenance of At~ prevents apoptosis. Since apoptosis is highly regulated and involves the activity of hydrolytic enzymes, chromatin condensation and vesicle formation apoptosis is likely to have a high energy demand. We propose that the cellular ATP level is an important determinant for cell death. This hypothesis is supported by circumstantial evidence, is consistent with the available data, has a corrolary in aging, and is amenable to direct experimental testing particularly with flow cytometry as a promising tool.

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“…These include hepatocytes (oxidative stress [92][93][94] ; anoxia [95] ; reoxygenation [96]), endothelial cells (reoxygenation [97]), heart (reperfusion [98]) and brain (transient ischaemia [99] ; Nmethyl--aspartate [100]). But as more has become known of CSA and its target proteins, it has become clear that CSA is a far from incisive means of diagnosing specific cellular events.…”

Section: ' Hotdogs ' With Calceinmentioning

confidence: 99%

The mitochondrial permeability transition pore and its role in cell death

Crompton

1999

Biochemical Journal

1,807

1,267

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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.

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Cyclosporin a protects hepatocytes against prooxidant-induced cell killing

Cited by 95 publications

References 45 publications

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

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

Control of apoptosis by the cellular ATP level

The mitochondrial permeability transition pore and its role in cell death

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Cyclosporin a protects hepatocytes against prooxidant-induced cell killing

Cited by 95 publications

References 45 publications

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

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

Control of apoptosis by the cellular ATP level

The mitochondrial permeability transition pore and its role in cell death

Contact Info

Product

Resources

About

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

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