Induction of the mitochondrial permeability transition by protease activity in rats: A mechanism of hepatocyte necrosis

Aguilar, Humberto; Botla, Ravi; Arora, Amindra S.; Bronk, Steven F.; Gores, Gregory J.

doi:10.1053/gast.1996.v110.pm8566604

Cited by 82 publications

(47 citation statements)

References 3 publications

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“…Calpain substrates include cytoskeletal, plasma membrane-associated proteins and signal transduction-and calmodulin-dependent proteins and transcription factors (41). Activation of a mitochondrial calpain-like protease activity in rat liver mitochondria can induce the mitochondrial permeability transition, a trigger for cell necrosis (42). Interestingly, cyclosporin A, an inhibitor of the mitochondrial permeability transition, decreased the Fe/AA toxicity in E47 cells (27).…”

Section: Discussionmentioning

confidence: 99%

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

Andrés

Cederbaum

2002

Journal of Biological Chemistry

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The objective of this work was to investigate whether CYP2E1-and oxidative stress-dependent toxicity in HepG2 cells is mediated by an increase of cytosolic Ca in the toxicity. Reactive oxygen production was similar in media with or without calcium, indicating that calcium was not modulating CYP2E1-dependent oxidative stress. Toxicity, lipid peroxidation, and the increase of Ca 2؉ in E47 cells exposed to iron-AA were inhibited by ␣-tocopherol. E47 cells (but not C34 cells) exposed to iron-AA showed increased calpain activity in situ (40-fold). The toxicity in E47 cells mirrorred calpain activation and was inhibited by calpeptin, suggesting that calpain activation plays a causal role in toxicity. These results suggest that CYP2E1-dependent toxicity in this model depends on the activation of lipid peroxidation, followed by an increased influx of extracellular Ca 2؉

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Section: Discussionmentioning

confidence: 99%

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

Andrés

Cederbaum

2002

Journal of Biological Chemistry

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“…Isolated rat liver mitochondria (1 mg/ml) were suspended in a buffer consisting of 200 mM sucrose, 10 mM Tris-MOPS, 5 mM succinate, 1 mM potassium phosphate, 2 M rotenone, 1 g/ml oligomycin, 10 M EGTA, pH 7.4, at 25°C as described before (42). Opening of the pore was induced by the ANT ligand, ATR (100 M), and prevented by preincubation with cyclosporin A (CSA) (5 M).…”

Section: Methodsmentioning

confidence: 99%

Cholesterol Impairs the Adenine Nucleotide Translocator-mediated Mitochondrial Permeability Transition through Altered Membrane Fluidity

Colell¹,

Garcı́a-Ruiz

Lluis³

et al. 2003

Journal of Biological Chemistry

124

103

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Mitochondrial permeability transition (MPT) has been proposed to play a key role in cell death. Downstream MPT events include the release of apoptogenic factors that sets in motion the mitochondrial apoptosome leading to caspase activation. The current work examined the regulation of MPT by membrane fluidity modulated upon cholesterol enrichment. Mitochondria enriched in cholesterol displayed increased microviscosity resulting in impaired MPT induced by atractyloside, a c-conformation stabilizing ligand of the adenine nucleotide translocator (ANT). This effect was dependent on the dose of cholesterol loaded and reversed upon the fluidization of mitochondria by the fatty acid derivative A 2 C. Mitoplasts derived from cholesterol-enriched mitochondria responded to atractyloside in a similar fashion as intact mitochondria, indicating that a significant amount of cholesterol is still found in the inner membrane. The effects of cholesterol on MPT induced by atractyloside were mirrored by the release of intermembrane proteins, cytochrome c, Smac/Diablo, and apoptosis inducing factor. However, cholesterol loading did not affect the uptake rate of adenine nucleotide hence dissociating the function of ANT as a MPT-mediated protein from its adenine nucleotide exchange function. Thus, these findings indicate that the ability of atractyloside to induce MPT via ANT requires an appropriate membrane fluidity range.

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“…Such effectors include divalent cations (calcium, magnesium) (Szabo Â et al, 1992), protons , the concentration of ATP and ADP, the NAD(P)H 2 /NAD(P) ratio, thiol redoxidation (Constantini et al, 1996), amphipathic peptides (Pfeiffer et al, 1995), fatty acids (Zoratti and Szabo Â , 1995), and perhaps calpain-like proteases (Aguilar et al, 1996). PT entails the free diffusion of solutes 51500 Da across the inner mitochondrial membrane, thus disrupting ipso facto the mitochondrial transmembrane potential (DC m ), which is essentially a proton gradient (Zoratti and Szabo Á , 1995).…”

Section: Criterion Of the Switchmentioning

confidence: 99%

Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution

1997

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Recent evidence indicates that a profound alteration in mitochondrial function constitutes an obligatory early event of the apoptotic process. The molecular mechanism accounting for this alteration is mitochondrial permeability transition (PT). PT is both sufficient and necessary for apoptosis to occur. Experiments performed in cell-free systems of apoptosis demonstrate that mitochondria undergoing PT release protease activators that can trigger nuclear manifestations of apoptotis. Bcl-2 and its homologs are endogenous regulators of PT. It appears that some types of necrosis, those inhibited by Bcl-2, involve PT. If PT is a rate-limiting event of both apoptosis and necrosis, then downstream events including caspase activation and the bioenergetic consequences of PT must determine the choice between both modes of cell death. PT without caspase activation would cause necrosis. These findings have important implications for the comprehension of the apoptotic process, for the dichotomy between apoptosis and necrosis, and for the phylogeny of programmed cell death. Apoptosis may have evolved together with the endosymbiotic incorporation of aerobic bacteria (the precursors of mitochondria) into ancestral unicellular eukaryotes.

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Induction of the mitochondrial permeability transition by protease activity in rats: A mechanism of hepatocyte necrosis

Cited by 82 publications

References 3 publications

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

Role of Calcium and Calcium-activated Proteases in CYP2E1-dependent Toxicity in HEPG2 Cells

Cholesterol Impairs the Adenine Nucleotide Translocator-mediated Mitochondrial Permeability Transition through Altered Membrane Fluidity

Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution

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