Increase in Intracellular Hydrogen Peroxide and Upregulation of a Nuclear Respiratory Gene Evoked by Impairment of Mitochondrial Electron Transfer in Human Cells

Suzuki, Hiroshi; Kumagai, Takeshi; Goto, Ayumu; Sugiura, Takuma

doi:10.1006/bbrc.1998.9181

Cited by 53 publications

(38 citation statements)

References 23 publications

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“…There is evidence for a mitochondrial-to-nuclear signal after inhibition of the electron transport chain that results in the regulation of nuclear-encoded transcripts (Suzuki et al, 1998;Brill and Bennett, 2003). Our analysis did not uncover changes in gene expression that directly link reduced ATP production and oxygen radical generation to the alteration of transcript levels at two time points after injury.…”

Section: Clustering Analysismentioning

confidence: 50%

Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra

Miller¹,

Callahan²,

Casaceli³

et al. 2004

J. Neurosci.

101

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Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death.

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Section: Clustering Analysismentioning

confidence: 50%

Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra

Miller¹,

Callahan²,

Casaceli³

et al. 2004

J. Neurosci.

101

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“…The alternative oxidase pathway has been shown to interact with the classic oxidative pathway to protect against ROS, produce intracellular signaling during stress, or generate energy in some biological systems (24,26,37). We did not specifically test the impact of the energy production aspects of the alternative oxidase pathway in C. neoformans, but our results suggest that it would play a very minor role, since the yeast was able to grow very well within the rabbit CSF.…”

Section: Discussionmentioning

confidence: 88%

Role of Alternative Oxidase Gene in Pathogenesis of Cryptococcus neoformans

et al. 2003

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We identified a homologue of the alternative oxidase gene in a screen to identify genes that are preferentially transcribed in response to a shift to 37°C in the human-pathogenic yeast Cryptococcus neoformans. Alternative oxidases are nucleus-encoded mitochondrial proteins that have two putative roles: they can function in parallel with the classic cytochrome oxidative pathway to produce ATP, and they may counter oxidative stress within the mitochondria. The C. neoformans alternative oxidase gene (AOX1) was found to exist as a single copy in the genome, and it encodes a putative protein of 401 amino acids. An aox1 mutant strain was created using targeted gene disruption, and the mutant strain was reconstituted to wild type using a full-length AOX1. Compared to both the wild-type and reconstituted strains, the aox1 mutant strain was not temperature sensitive but did have significant impairment of both respiration and growth when treated with inhibitors of the classic cytochrome oxidative pathway. The aox1 mutant strain was also found to be more sensitive to the oxidative stressor tert-butyl hydroperoxide. The aox1 mutant strain was significantly less virulent than both the wild type and the reconstituted strain in the murine inhalational model, and it also had significantly impaired growth within a macrophage-like cell line. These data demonstrate that the alternative oxidase of C. neoformans can make a significant contribution to metabolism, has a role in the yeast's defense against exogenous oxidative stress, and contributes to the virulence composite of this organism, possibly by improving survival within phagocytic cells.Cryptococcus neoformans is a basidiomycetous fungus and a major human pathogen. This pathogenic fungus has a wide human host range by producing infections in both immunocompromised and immunocompetent hosts (6). Understanding the mechanisms of how this encapsulated yeast can so effectively attack a susceptible host has received renewed attention as the infrastructure for molecular biology of this yeast has matured. Several phenotypic factors in the virulence composite, such as formation of a polysaccharide capsule (7), melanin production (45), urease synthesis (11), phospholipase secretion (10), mannose production (46), high-temperature growth (28), and several signaling molecules and pathways for these factors (44,28

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“…However, treatment of the tissues with NAC fully reversed the E GSH to normality, but normalization of the redox status did not modify their neurosecretory power. These last observations coupled to the well known ability of NAC to buffer the increased production of ROS induced by complex III and IV inhibitors in many cell systems (Watabe and Nakaki, 2007;Stöckl et al, 2006;Suzuki et al, 1998;Satpute et al, 2008;Zhang et al, 2007), would indicate that there is not any relationship between ROS levels and chemoreceptor cell activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

Gomez-Niño

Agapito

Obeso

et al. 2009

Respiratory Physiology & Neurobiology

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a b s t r a c tLow oxygen sensing in chemoreceptor cells involves the inhibition of specific plasma membrane K + channels, suggesting that mitochondria-derived reactive oxygen species (ROS) link hypoxia to K + channel inhibition, subsequent cell depolarization and activation of neurotransmitter release. We have used several mitochondrial poisons, alone and in combination with the antioxidant N-acetylcysteine (NAC), and quantify their capacity to alter GSH/GSSG levels and glutathione redox potential (E GSH ) in rat diaphragm. Selected concentrations of mitochondrial poisons with or without NAC were tested for their capacity to activate neurotransmitter release in chemoreceptor cells and to alter ATP levels in intact rat carotid body (CB). We found that rotenone (1 M), antimycin A (0.2 g/ml) and sodium azide (5 mM) decreased E GSH ; NAC restored E GSH to control values. At those concentrations mitochondrial poisons activated neurotransmitter release from CB chemoreceptor cells and decreased CB ATP levels, NAC being ineffective to modify these responses. Additional experiments with 3-nitroprionate (5 mM), lower concentrations of rotenone and dinitrophenol revealed variable relationships between E GSH and chemoreceptor cell neurotransmitter release responses and ATP levels. These findings indicate a lack of correlation between mitochondrialgenerated modifications of E GSH and chemoreceptor cells activity. This lack of correlation renders unlikely that alteration of mitochondrial production of ROS is the physiological pathway chemoreceptor cells use to signal hypoxia.

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Increase in Intracellular Hydrogen Peroxide and Upregulation of a Nuclear Respiratory Gene Evoked by Impairment of Mitochondrial Electron Transfer in Human Cells

Cited by 53 publications

References 23 publications

Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra

Dysregulation of Gene Expression in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Substantia Nigra

Role of Alternative Oxidase Gene in Pathogenesis of Cryptococcus neoformans

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

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