Menadione-(2-methyl-1,4-naphthoquinone) dependent enzymic redox cycling and calcium release by mitochondria

Frei, Balz; Winterhalter, Kaspar H.; Richter, Christoph

doi:10.1021/bi00363a040

Cited by 96 publications

(44 citation statements)

References 22 publications

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“…We then examined whether the deficiency in OGG1 altered susceptibility to cell death caused by 2-methyl-1. 4-naphthoquinone (menadione), which produces ROS within cells (Supplementary Figure S2; Frei et al, 1986). The median lethal dose of menadione (LD 50 ¼18.5 mM) for Ogg1 À/À MEFs was significantly lower than that for the wild type (32 mM) ( Figure 1A).…”

Section: Ogg1mentioning

confidence: 99%

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Oka

Ohno

Tsuchimoto

et al. 2008

EMBO J

199

205

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Oxidative base lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial DNAs under oxidative stress, resulting in cell death. However, it is not known which form of DNA is involved, whether nuclear or mitochondrial, nor is it known how the death order is executed. We established cells which selectively accumulate 8-oxoG in either type of DNA by expression of a nuclear or mitochondrial form of human 8-oxoG DNA glycosylase in OGG1-null mouse cells. The accumulation of 8-oxoG in nuclear DNA caused poly-ADP-ribose polymerase (PARP)-dependent nuclear translocation of apoptosis-inducing factor, whereas that in mitochondrial DNA caused mitochondrial dysfunction and Ca 2 þ release, thereby activating calpain. Both cell deaths were triggered by single-strand breaks (SSBs) that had accumulated in the respective DNAs, and were suppressed by knockdown of adenine DNA glycosylase encoded by MutY homolog, thus indicating that excision of adenine opposite 8-oxoG lead to the accumulation of SSBs in each type of DNA. SSBs in nuclear DNA activated PARP, whereas those in mitochondrial DNA caused their depletion, thereby initiating the two distinct pathways of cell death.

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Section: Ogg1mentioning

confidence: 99%

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Oka

Ohno

Tsuchimoto

et al. 2008

EMBO J

199

205

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“…We previously demonstrated that menadione caused similar substrate proteolysis (p53 and atypical PARP cleavage) in NQO1-deficient cells, or at high doses in cells that express NQO1 where detoxification processes were over-ridden (5). 3 The semiquinone form of menadione can undergo spontaneous oxidation to the parent quinone (59,63,65,66); a pattern similar to the futile cycling observed after ␤-Lap bioactivation by NQO1 (5). Loss of reducing equivalents, such as NADH, due to the futile cycling of menadione may cause inactivation of the electron transport chain with the concomitant loss of mitochondrial membrane potential, and thus, loss of ATP (67,68).…”

Section: Camentioning

confidence: 99%

Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death

Tagliarino¹,

Pink²,

Dubyak

et al. 2001

Journal of Biological Chemistry

153

150

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␤-Lapachone (␤-Lap) triggers apoptosis in a number of human breast and prostate cancer cell lines through a unique apoptotic pathway that is dependent upon NQO1, a two-electron reductase. Downstream signaling pathway(s) that initiate apoptosis following treatment with ␤-Lap have not been elucidated. Since calpain activation was suspected in ␤-Lap-mediated apoptosis, we examined alterations in Ca 2؉ homeostasis using NQO1-expressing MCF-7 cells. ␤-Lap-exposed MCF-7 cells exhibited an early increase in intracellular cytosolic Ca 2؉, from endoplasmic reticulum Ca 2؉ stores, comparable to thapsigargin exposures. 1,2-Bis-(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethyl ester, an intracellular Ca 2؉ chelator, blocked early increases in Ca 2؉ levels and inhibited ␤-Lap-mediated mitochondrial membrane depolarization, intracellular ATP depletion, specific and unique substrate proteolysis, and apoptosis. The extracellular Ca 2؉ chelator, EGTA, inhibited later apoptotic end points (observed >8 h, e.g. substrate proteolysis and DNA fragmentation), suggesting that later execution events were triggered by Ca 2؉ influxes from the extracellular milieu. Collectively, these data suggest a critical, but not sole, role for Ca 2؉ in the NQO1-dependent cell death pathway initiated by ␤-Lap. Use of ␤-Lap to trigger an apparently novel, calpain-like-mediated apoptotic cell death could be useful for breast and prostate cancer therapy. ␤-Lap1 is a naturally occurring compound present in the bark of the South American Lapacho tree. It has antitumor activity against a variety of human cancers, including colon, prostrate, promyelocytic leukemia, and breast (1-3). ␤-Lap was an effective agent (alone and in combination with taxol) against human ovarian and prostate xenografts in mice, with little host toxicity (4). We recently demonstrated that ␤-Lap kills human breast and prostate cancer cells by apoptosis, a cytotoxic response significantly enhanced by NAD(P)H:quinone oxidoreductase (NQO1, E.C. 1.6.99.2) enzymatic activity (5).2 ␤-Lap cytotoxicity was prevented by co-treatment with dicumarol (an NQO1 inhibitor) in NQO1-expressing breast and prostate cancer cells (5).2 NQO1 is a cytosolic enzyme elevated in breast cancers (6) that catalyzes a two-electron reduction of quinones (e.g. ␤-Lap, menadione), utilizing either NADH or NADPH as electron donors. Reduction of ␤-Lap by NQO1 presumably leads to a futile cycling of the compound, wherein the quinone and hydroquinone form a redox cycle with a net concomitant loss of reduced NAD(P)H (5).Apoptosis is an evolutionarily conserved pathway of biochemical and molecular events that underlie cell death processes involving the stimulation of intracellular zymogens. The process is a genetically programmed form of cell death involved in development, normal turnover of cells, and in cytotoxic responses to cellular insults. Once apoptosis is initiated, biochemical and morphological changes occur in the cell. These changes include: DNA fragmentation, chromatin condensation, cytoplasmic membran...

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“…To investigate in greater depth the involvement of free radical injury in the pathogenesis of the cardiomyopathy with cataracts and complex I deficiency, skin fibroblasts from a group of patients were assessed for hydroxyl radical production and aldehydic lipid peroxidation products with and without redox active agents known to cause cell injury by free radical-mediated mechanisms (18,19).…”

Section: Introductionmentioning

confidence: 99%

Excessive formation of hydroxyl radicals and aldehydic lipid peroxidation products in cultured skin fibroblasts from patients with complex I deficiency.

Luo¹,

Pitkänen²,

Kassovska-Bratinova³

et al. 1997

J. Clin. Invest.

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Previous studies suggest oxygen free radicals' involvement in the etiology of cardiomyopathy with cataracts. To investigate the role of free radicals in the pathogenesis of the cardiomyopathy with cataracts and complex I deficiency, fibroblasts from patients were assessed for hydroxyl radical formation and aldehydic lipid peroxidation products with and without redox active agents that increase free radicals. The rate of hydroxyl radical formation in patient cells was increased over 2-10-fold under basal conditions, and up to 20-fold after menadione or doxorubicin treatment compared with normal cells. We also found an overproduction of aldehydes in patient cells both under basal conditions and after treatment. Both hydroxyl radicals and toxic aldehydes such as hexanal, 4-hydroxynon-2-enal, and malondialdehyde were elevated in cells from patients with three types of complex I deficiency. In contrast, acyloins, the less toxic conjugated products of pyruvate and saturated aldehydes, were lower in the patient cells.Our data provide direct evidence for the first time that complex I deficiency is associated with excessive production of hydroxyl radicals and lipid peroxidation. The resultant damage may contribute to the early onset of cardiomyopathy and cataracts and death in early infancy in affected patients with this disease. ( J. Clin. Invest. 1997. 99:2877 -2882.)

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Menadione-(2-methyl-1,4-naphthoquinone) dependent enzymic redox cycling and calcium release by mitochondria

Cited by 96 publications

References 22 publications

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death

Excessive formation of hydroxyl radicals and aldehydic lipid peroxidation products in cultured skin fibroblasts from patients with complex I deficiency.

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