Critical Role of Reactive Oxygen Species and Mitochondrial Permeability Transition in Microcystin-Induced Rapid Apoptosis in Rat Hepatocytes

Ding, Wen–Xing; Shen, Han‐Ming; Ong, Choon‐Nam

doi:10.1053/jhep.2000.16183

Cited by 227 publications

(157 citation statements)

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“…14 It has also recently been postulated that CaMKII is activated late in the process of microcystin-induced apoptosis through increase of intracellular Ca 2 þ secondary to severe mitochondrial damage. 15,16 This would imply that CaMKII only has a role late in the downstream apoptosis signaling modulating the phenotype of PP-inhibitor-induced death.…”

Section: Introductionmentioning

confidence: 99%

CaM-kinaseII-dependent commitment to microcystin-induced apoptosis is coupled to cell budding, but not to shrinkage or chromatin hypercondensation

et al. 2005

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The protein phosphatase inhibitor microcystin-LR (MC) induced hepatocyte apoptosis mediated by the calciumcalmodulin-dependent multifunctional protein kinase II (CaM-KII). CaMKII antagonists were added at various times after MC to define for how long the cells depended on CaMKII activity to be committed to execute the various parameters of death. Shrinkage and nonpolarized budding were reversible and not coupled to commitment. A critical commitment step was observed 15-20 min after MC (0.5 lM) addition. After this, CaMKII inhibitors no longer protected against polarized budding, DNA fragmentation, lost protein synthesis capability, and cell disruption. Commitment to chromatin hypercondensation occurred 40 min after MC addition. In conclusion, irreversible death commitment was coupled to polarized budding, but not to shrinkage or chromatin condensation. Antioxidant prevented chromatin condensation when given after the CaMKII-dependent commitment point, suggesting that CaMKII had mediated the accumulation of a second messenger of reactive oxygen species nature.

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Section: Introductionmentioning

confidence: 99%

CaM-kinaseII-dependent commitment to microcystin-induced apoptosis is coupled to cell budding, but not to shrinkage or chromatin hypercondensation

et al. 2005

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“…Involvement of mitochondria, including an increase of reactive oxygen species followed by a loss of mitochondrial membrane potential was observed (Ding et al, 2000). Moreover, mitochondria have been found to be one of the major targets in the MC-LR induced apoptotic process, and the onset of mitochondrial permeability transition (MPT) precedes the characteristic signs of apoptosis (Ding et al, 2000). Ding et al (2001) showed that MC-LR caused an early surge of mitochondrial Ca 2+ prior to the onset of MPT and cell death in MC-LR treated rat hepatocytes.…”

Section: Introductionmentioning

confidence: 98%

“…inhibition of serine/threonine phosphatases-1 and -2A (Mackintosh et al, 1990) and/or to the increased formation of reactive oxygen species (Ding et al, 2000). Cytoskeletal changes and apoptosis induced by microcystins were found in experiments on cultured rat hepatocytes and kidney cells (Eriksson et al, 1989;Falconer and Yeung, 1992;Wickstrom et al, 1995).…”

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confidence: 94%

“…However, the exact mechanisms underlying the suggested apoptosis-induced potential are still unknown. Involvement of mitochondria, including an increase of reactive oxygen species followed by a loss of mitochondrial membrane potential was observed (Ding et al, 2000). Moreover, mitochondria have been found to be one of the major targets in the MC-LR induced apoptotic process, and the onset of mitochondrial permeability transition (MPT) precedes the characteristic signs of apoptosis (Ding et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…They have demonstrated that in the intestine microcystin-LR and supernatants of macroph-ages stimulated by this toxin were capable of promoting water and electrolytes secretion (Nobre et al, 2004). Acute exposure to MC-LR results in a decrease in the antioxidant enzymes and an increase in lipid peroxidation in rat liver and kidneys, suggesting that oxidative stress has an important role in the pathogenesis of MC-LR-induced toxicity (Ding et al, 1998(Ding et al, , 2000Moreno et al, 2005). Microcystin-LR induces apoptosis in human derived CaCo 2 cell lines and MCF-7 cells via a mechanism similar to that observed for primary rat hepatocytes (Botha et al, 2004).…”

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confidence: 99%

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Mitochondria a key role in microcystin‐LR kidney intoxication

La-Salete

Oliveira

Palmeira

et al. 2007

J of Applied Toxicology

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Microcystins (MCs) are a group of closely related cyclic heptapeptides produced by a variety of common cyanobacteria. These toxins have been implicated in both human and livestock mortality. Microcystin-LR could affect renal physiology by altering vascular, glomerular and urinary parameters, indicating that MC-LR could act directly on the kidney. The aim of the current work was to examine the effect of MC-LR on mitochondrial oxidative phosphorylation of rat kidney isolated mitochondria.Furthermore, microcystin-LR decreased both state 3 and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled respiration. The transmembrane potential was strongly depressed by MC-LR in a concentration dependent manner, pointing to an uncoupling effect; however, microcystin-LR did not increase the permeability of the inner mitochondria membrane to protons. Therefore, the transmembrane decrease was a consequence of a strong inhibitory effect on redox complexes. The addition of uncoupling concentrations of MC-LR to Ca 2+ + + + + -loaded mitochondria treated with ruthenium red resulted in mitochondrial permeability transition pore (MPTP) opening, as evidenced by mitochondrial swelling in isosmotic sucrose medium. Mitochondrial swelling in the presence of Ca 2+ + + + + was prevented by cyclosporin A and was drastically inhibited by catalase and dithiothreitol, indicating the participation of mitochondrial generated reactive oxygen species in this process. From this study it can be concluded that the bioenergetic lesion promoted by microcystin-LR seems to be sufficient to explain renal injury.

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Mechanism of action of the antifibrogenic compound gliotoxin in rat liver cells

et al. 2004

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Gliotoxin has been shown to promote a reversal of liver fibrosis in an animal model of the disease although its mechanism of action in the liver is poorly defined. The effects of gliotoxin on activated hepatic stellate cells (HSCs) and hepatocytes have therefore been examined. Addition of gliotoxin (1.5 M) to culture-activated HSCs resulted in its rapid accumulation, resulting in increased levels of glutathione and apoptosis without any evidence of oxidative stress. In contrast, although hepatocytes also rapidly sequestered gliotoxin, cell death only occurred at high (50-M) concentrations of gliotoxin and by necrosis. At high concentrations, gliotoxin was metabolized by hepatocytes to a reduced (dithiol) metabolite and glutathione was rapidly oxidized. Fluorescent dye loading experiments showed that gliotoxin caused oxidative stress in hepatocytes. Antioxidants-but not thiol redox active compounds-inhibited both oxidative stress and necrosis in hepatocytes. In contrast, HSC apoptosis was not affected by antioxidants but was potently abrogated by thiol redox active compounds. The adenine nucleotide transporter (ANT) is implicated in mitochondrial-dependent apoptosis. HSCs expressed predominantly nonliver ANT isoform 1, and gliotoxin treatment resulted in a thiol redox-dependent alteration in ANT mobility in HSC extracts, but not hepatocyte extracts. In conclusion, these data suggest that gliotoxin stimulates the apoptosis of HSCs through a specific thiol redox-dependent interaction with the ANT. Further understanding of this mechanism of cell death will aid in finding therapeutics that specifically stimulate HSC apoptosis in the liver, a promising approach to antifibrotic therapy. Supplementary material for this article can be found on the HEPATOLOGY website

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Critical Role of Reactive Oxygen Species and Mitochondrial Permeability Transition in Microcystin-Induced Rapid Apoptosis in Rat Hepatocytes

Cited by 227 publications

References 41 publications

CaM-kinaseII-dependent commitment to microcystin-induced apoptosis is coupled to cell budding, but not to shrinkage or chromatin hypercondensation

CaM-kinaseII-dependent commitment to microcystin-induced apoptosis is coupled to cell budding, but not to shrinkage or chromatin hypercondensation

Mitochondria a key role in microcystin‐LR kidney intoxication

Mechanism of action of the antifibrogenic compound gliotoxin in rat liver cells

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