Nitric Oxide and Mitochondrial Respiration

Brown, Guy C.; McBride, Alan G.; McNaught, Kevin St. P.; Borutaite, Vilma

doi:10.1042/bst025383sa

Cited by 103 publications

(148 citation statements)

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“…NO can induce apoptosis in a variety of cell lines including macrophages, thymocytes, T cells, myeloid cells. Low concentrations of NO may specifically inhibit cytochrome c oxidase, leading to ATP depletion [58]. A site for NO modulation of the apoptotic process that has received little attention is the controlled release of cytochrome c from the mitochondria [59].…”

Section: Mitochondrial Oxidative Stressmentioning

confidence: 99%

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

Nagy

Koncz

Fernández

et al. 2007

Free Radical Biology and Medicine

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T lymphocyte activation is associated with nitric oxide (NO) production that plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both T lymphocyte activation and apoptosis, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus (SLE) induces mitochondrial biogenesis and alters Ca 2+ signaling. Thus, while NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity.

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Section: Mitochondrial Oxidative Stressmentioning

confidence: 99%

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

Nagy

Koncz

Fernández

et al. 2007

Free Radical Biology and Medicine

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“…Normal tissue levels of NO and O 2 are 100 -500 nM and 30 M, respectively. This ratio of NO/O 2 causes approximately halfmaximal inhibition of mitochondrial respiration rate, suggesting that NO serves to tonically inhibit respiration [Brown, 1999]. But NO also reacts with O 2 − to form ONOO − , which causes irreversible inhibition of mitochondrial respiration thereby damaging all components of the ETC.…”

Section: Mostmentioning

confidence: 99%

“…But NO also reacts with O 2 − to form ONOO − , which causes irreversible inhibition of mitochondrial respiration thereby damaging all components of the ETC. Also, ONOO − induces mitochondrial swelling, depolarization, Ca 2 + release, PTP activation, and apoptosis [Brown, 1999].…”

Section: Mostmentioning

confidence: 99%

Melatonin, mitochondria, and cellular bioenergetics

Acuña-Castroviejo

Martı́n

Macías

et al. 2001

Journal of Pineal Research

383

313

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Aerobic cells use oxygen for the production of 90-95% of the total amount of ATP that they use. This amounts to about 40 kg ATP/day in an adult human. The synthesis of ATP via the mitochondrial respiratory chain is the result of electron transport across the electron transport chain coupled to oxidative phosphorylation. Although ideally all the oxygen should be reduced to water by a four-electron reduction reaction driven by the cytochrome oxidase, under normal conditions a small percentage of oxygen may be reduced by one, two, or three electrons only, yielding superoxide anion, hydrogen peroxide, and the hydroxyl radical, respectively. The main radical produced by mitochondria is superoxide anion and the intramitochondrial antioxidant systems should scavenge this radical to avoid oxidative damage, which leads to impaired ATP production.

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“…Mitochondrial hyperpolarization (MHP), an early event of T-cell activation and death, appears to be mediated through inhibition of F 0 F 1 -ATPase or dephosphorylation of cytochrome c oxidase [44]. Nitric oxide (NO), acting as a competitive antagonist of oxygen, can also reversibly inhibit cytochrome c oxidase and cause MHP [69]. Using the energy of ATP, F 0 F 1 -ATPase can pump protons out of the mitochondrial matrix into the intermembrane space, thus causing ΔΨ m elevation.…”

Section: Box 1 Regulation Of the Mitochondrial Transmembrane Potentimentioning

confidence: 99%

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

220

142

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T-cell activation, proliferation and selection of the cell death pathway depend on the production of reactive oxygen intermediates (ROIs) and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T cells of patients with systemic lupus erythematosus (SLE) exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production and depleted ATP, which mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and might account for increased interferon a production and inflammation in lupus patients. MHP is proposed as a key mechanism of SLE pathogenesis and is therefore a target for pharmacological intervention.Innate and adaptive immune responses depend on controlled production of ATP and reactive oxygen intermediates (ROIs) in mitochondria. In response to antigenic stimulation, clonal expansion of T and B cells are continuously downsized and potentially autoreactive cells are eliminated by apoptosis. An array of signals through the T-cell receptor (TCR), costimulatory molecules, cell death receptors, lymphokines, and other circulating metabolites, such as ATP, NAD, cADPR, glucose, glutathione, nitric oxide (NO) and ROIs, determine the fate of T cells [1]. T-cell activation and death pathway selection depend on the production of ROIs and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ) (Box 1). Disruption of ΔΨ m has been proposed as the point of no return in apoptotic signaling [2] T-cell activation is regulated by mitochondrial ROI productionROIs modulate T-cell activation, cytokine production and proliferation at multiple levels [12]. The antigen-binding αβ or γδTCR is associated with a multimeric receptor module comprising the CD3γδε and TCRζ chains. The cytoplasmic domains of the CD3 and ζ chains contain a common motif, termed the immunoreceptor tyrosinebased activation motif (ITAM), which is crucial for the coupling of intracellular tyrosine kinases [13]. . Thus, expression of cytokines can be selectively regulated by oxidative stress depending on the relative expression level of transcription factors involved (e.g. IL-2 is expressed through a promoter that has AP-1 and NFAT motifs, and IL-4 is expressed through an AP-1-less NFAT enhancer; Figure 1). Redox control of apoptosis signal processingProgrammed cell death (PCD) or apoptosis is a physiological mechanism for elimination of autoreactive lymphocytes during development. Signaling through the Fas or structurally related TNF family of cell-surface death receptors has emerged as a major pathway in the elimination of unwanted cells under physiological and disease conditions [18]. Fas and TNF receptors mediate cell death through cytoplasmic death domains (DDs) shared by both receptors [19]. They ...

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Nitric Oxide and Mitochondrial Respiration

Cited by 103 publications

References 0 publications

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

Melatonin, mitochondria, and cellular bioenergetics

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

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