Nitric Oxide, Mitochondria, and Cell Death

Brown, Guy C.; Borutaitė, Vilmantė

doi:10.1080/15216540152845993

Cited by 159 publications

(109 citation statements)

References 75 publications

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“…In contrast, others have reported that NO inhibits mitochondrial respiration through two distinct pathways. 114,115 Reversible inhibition of cytochrome oxidase was seen with low concentrations of NO, whereas higher concentrations caused an inhibition of alternative respiratory chain complexes. 115 Inhibition of complex IV was reversible, whereas inhibition of complex I was irreversible.…”

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

“…114,115 Reversible inhibition of cytochrome oxidase was seen with low concentrations of NO, whereas higher concentrations caused an inhibition of alternative respiratory chain complexes. 115 Inhibition of complex IV was reversible, whereas inhibition of complex I was irreversible. 114 Of course, the mechanisms described above may not be mutually exclusive.…”

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

“…For example, respiratory inhibition by NO may enhance the production of reactive oxygen species by mitochondria, leading to the formation of ONOO À and providing an ONOO À -mediated pathway for NO-induced cytotoxicity (Figure 2). 115 …”

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

“…33 ONOO À has been shown to reversibly or irreversibly inhibit a number of mitochondrial respiratory complexes as well as inducing mitochondrial swelling, depolarisation, calcium release and permeability transition. 114,115 Macrophage apoptosis can also be induced by exposure to ONOO À , via oxidative stress, which can be reduced by antioxidants such as ascorbic acid or phytolens. 30,116 Induction of apoptosis by NO in elicited murine macrophages or RAW 264.7 cells has also been attributed to the formation of ONOO À within mitochondria, as nitrotyrosine residues were detected in cytochrome c. 23 ONOO À and metabolites of NO (e.g.…”

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

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Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

et al. 2003

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Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Many factors are able to influence the rate of apoptosis in neutrophils, eosinophils, monocytes and macrophages. Among these is the signalling molecule nitric oxide (NO), which possesses both anti-and proapoptotic properties, depending on the concentration and flux of NO, and also the source from which NO is derived. This review summarises the differential effects of NO on inflammatory cell apoptosis and outlines potential mechanisms that have been proposed to explain such actions.

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Section: Proapoptotic Mechanismsmentioning

confidence: 99%

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

Section: Proapoptotic Mechanismsmentioning

confidence: 99%

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Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

et al. 2003

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“…Nitric oxide can directly modulate cell function via inhibition of mitochondrial respiration but conversion to peroxynitrite in the presence of superoxide also appears to underlie many of its deleterious effects (Beckman et al, 1990;Brown and Borutaite, 2001). Peroxynitrite and its degradation products can modify many cellular components (Goldstein et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Highly Selective and Prolonged Depletion of Mitochondrial Glutathione in Astrocytes Markedly Increases Sensitivity to Peroxynitrite

Muyderman¹,

Nilsson²,

Sims³

2004

J. Neurosci.

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Glutathione, a major endogenous antioxidant, is found in two intracellular pools in the cytoplasm and the mitochondria. To investigate the importance of the smaller mitochondrial pool, we developed conditions based on treatment with ethacrynic acid that produced near-complete and highly selective depletion of mitochondrial glutathione in cultured astrocytes. Recovery of mitochondrial glutathione was only partial over several hours, suggesting slow net uptake from the cytoplasm. Glutathione depletion alone did not significantly affect mitochondrial membrane potential, ATP content, or cell viability when assessed after 24 hr, although the activities of respiratory chain complexes were altered. However, these astrocytes showed a greatly enhanced sensitivity to 3-morpholinosydnonimine, a peroxynitrite generator. Treatment with 200 M 3-morpholinosydnonimine produced decreases within 3 hr in mitochondrial membrane potential and ATP content and caused the release of lactate dehydrogenase, contrasting with preservation of these properties in control cells. These properties deteriorated further by 24 hr in the glutathione-depleted cells and were associated with morphological changes indicative of necrotic cell death. This treatment enhanced the alterations in activities of the respiratory chain complexes observed with glutathione depletion alone. Cell viability was markedly improved by cyclosporin A, suggesting a role for the mitochondrial permeability transition in the astrocytic death. These studies provide the most direct evidence available for any cell type on the roles of mitochondrial glutathione. They demonstrate the critical importance of this metabolite pool in protecting against peroxynitrite-induced damage in astrocytes and indicate a key contribution in determining the activities of respiratory chain components.

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