Ca2+ release from mitochondria induced by prooxidants

Richter, Christoph; Frei, Balz

doi:10.1016/0891-5849(88)90088-3

Cited by 165 publications

(68 citation statements)

References 63 publications

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“…Under aerobic conditions, the respiratory chain is a potent source of free radical (33,37,38). A CI impairment leads to enhanced formation of ROS, as has been shown in submitochondrial particles (16,18) and in different cell systems (39,40).…”

Section: Discussionmentioning

confidence: 99%

Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology

Barrientos

Moraes

1999

Journal of Biological Chemistry

355

217

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The mitochondrial oxidative phosphorylation system consists of five multimeric enzymes (complexes I-V). NADH dehydrogenase or complex I (CI) is affected in most of the mitochondrial diseases and in some neurodegenerative disorders. We have studied the physiological consequences of a partial CI inhibition at the cellular level. We used a genetic model (40% CI-inhibited human-ape xenomitochondrial cybrids) and a drug-induced model (0 -100% CI-inhibited cells using different concentrations of rotenone). We observed a quantitative correlation between the level of CI impairment and cell respiration, cell growth, free radical production, lipid peroxidation, mitochondrial membrane potential, and apoptosis. We showed that cell death was quantitatively associated with free radical production rather than with a decrease in respiratory chain function. The results obtained with human xenomitochondrial cybrid cells were compatible with those observed in rotenoneinduced 40% CI-inhibited cells. At high concentrations (5-6-fold higher than the concentration necessary for 100% CI inhibition), rotenone showed a second toxic effect at the level of microtubule assembly, which also led to apoptosis. The correlation found among all the parameters studied helped clarify the physiological consequences of partial CI inhibitions at the cellular level.

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Section: Discussionmentioning

confidence: 99%

Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology

Barrientos

Moraes

1999

Journal of Biological Chemistry

355

217

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“…Reduced GSH and its precursor NAC are recognized as highly effective antioxidants, and have been shown to protect against neuronal degeneration in the 6-OHDA-challenged rat striatum (Froissard et al, 1997). The disruption of mitochondrial Ca 2+ homeostasis has been suggested to be a major cause of cell damage during conditions of oxidative stress (Richter and Frei, 1988;Kim et al, 1998). In addition, it has been reported that 6-OHDA induces Ca 2+ release from mitochondria (Reynolds, 1999;Bae et al, 2003;Jambrina et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Park

Lee²,

Park³

et al. 2007

Exp Mol Med

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Abstract6-Hydroxydopamine (6-OHDA) is a neurotoxin and is commonly used to generate experimental models of Parkinson's disease (PD). In this study, we investigated the signaling molecules involved in the 6-OHDA-induced cell death using a neuronal catecholaminergic cell line (SK-N-SH cells), and the protective effect of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-OHDA-induced neuronal death. 6-OHDA significantly increased levels of reactive oxygen species (ROS), intracellular Ca 2+ ([Ca 2+ ] i ), and p38 phosphorylation. In addition, this ROS increase by 6-OHDA was reduced by pretreatment with N-acetylcysteine (NAC), a free radical scavenger, but not by bis-(o-aminophenoxy)-ethane-N,N,N,Ntetraacetic acid (BAPTA), a Ca 2+ chelator. However, the [Ca 2+ ] i increase induced by 6-OHDA was suppressed by NAC. Moreover, pretreatment with NAC or BAPTA significantly prevented the 6-OHDAinduced increases in p38 phosphorylation, Bax/ Bcl-2 ratio, and caspase-3 activity. Although 6-OHDA-increased phosphorylation of p38 was prevented by NAC or BAPTA, inhibition of p38 by SB203580 did not suppress ROS, Bax/Bcl-2 ratio, or caspase-3 activity increases, and only partially prevented 6-OHDA-induced cell death, thus demonstrating that p38 activation is a component of a signaling pathway leading to the initiation of 6-OHDA-induced cell death, which acts in parallel with an ROS-Ca 2+ -Bcl-2-caspase-3 pathway. Moreover, fustin not only suppressed 6-OHDA-induced cell death in a concentration-dependent manner but also blocked 6-OHDA-induced increases in ROS, [Ca 2+ ] i , Bax/Bcl-2 ratio, caspase-3 activity, and p38 phosphorylation. These results suggest that fustin exerts neuroprotection against 6-OHDA-induced cell death.

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“…Treatment of rats with MP has been shown to form reactive metabolites that covalently bind specifically to mitochondrial proteins (50) and damage to the inner mitochondrial membrane has been proposed to play a significant role in MP toxicity (51,60). Co-incubation of MP-treated hepatocytes with phenylalkylamine Ca ++ channel blocker verapamil, but not treating the cells in a nominally Ca ++ -free medium, abrogated cell death and afforded approximately a 100-fold protection against MP effects suggesting that intracellular Ca ++ is involved in MP-induced cell death (44).…”

Section: Hamadeh Et Al Toxicologic Pathologymentioning

confidence: 99%

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

et al. 2002

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Methapyrilene (MP) exposure of animals can result in an array of adverse pathological responses including hepatotoxicity. This study investigates gene expression and histopathological alterations in response to MP treatment in order to 1) utilize computational approaches to classify samples derived from livers of MP treated rats based on severity of toxicity incurred in the corresponding tissue, 2) to phenotypically anchor gene expression patterns, and 3) to gain insight into mechanism(s) of methapyrilene hepatotoxicity. Large-scale differential gene expression levels associated with the exposure of male Sprague-Dawley rats to the rodent hepatic carcinogen MP for 1, 3, or 7 days after daily dosage with 10 or 100 mg/kg/day were monitored. Hierarchical clustering and principal component analysis were successful in classifying samples in agreement with microscopic observations and revealed low-dose effects that were not observed histopathologically. Data from cDNA microarray analysis corroborated observed histopathological alterations such as hepatocellular necrosis, bile duct hyperplasia, microvesicular vacuolization, and portal inflammation observed in the livers of MP exposed rats and provided insight into the role of specific genes in the studied toxicological processes.Keywords. Toxicogenomics; gene expression; methapyrilene; toxicity classification; rat liver; histopathology; phenotypic anchorage; hepatotoxicity.INTRODUCTION Methapyrilene (MP) is an antihistaminic compound once used as a popular over-the-counter sleep-aid component and also used in cold and allergy medications. It was found to induce hepatocellular carcinomas and cholangiocarcinomas in rats (20, 31, 33) and was subsequently withdrawn from the market. However, its carcinogenicity appears to be species-specific because no evidence has been found of MPassociated carcinogenesis in mice (3), guinea pigs, hamsters (32), or humans (36).MP was negative in the DNA adduct formation assay (8, 9, 34) and has not been found to be mutagenic with the Ames assay or other mutation assays (7, 38). Furthermore, MP did not induce unscheduled DNA synthesis (4) and did not cause sister-chromatid exchange (24). These data are consistent with the hypothesis that MP is carcinogenic in rats via nonmutagenic mechanisms (36,54). MP is extensively metabolized by the liver (29, 53), and phase I metabolism plays a major role in its toxicity because cytochrome P450 inhibitors afford protection from the toxicity of MP (43). The oxidative potential of methapyrilene and/or metabolites and increased cellular proliferation have been proposed to play a central role in the observed toxicity (9,45,49). Bile duct cannulation of MP treated rats affords protection from MP hepatic toxicity suggesting that enterohepatic recirculation of glucuronidated metabolites plays a role in MP toxicity (45). In humans, methapyrilene has a very short half-life, a relatively high apparent volume of distribution, and total

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Ca2+ release from mitochondria induced by prooxidants

Cited by 165 publications

References 63 publications

Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology

Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology

Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death

Methapyrilene Toxicity: Anchorage of Pathologic Observations to Gene Expression Alterations

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