In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain

Zhang, Surong; Fu, Junjie; Zhou, Zhenming

doi:10.1016/j.tiv.2003.09.002

Cited by 142 publications

(75 citation statements)

References 29 publications

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“…Our findings on mitochondrial ROS production conform to current literature: blockers of the respiratory chain cause a decrease in E GSH , albeit with different potencies, while the uncoupler did not measurably alter ROS production (Votyakova and Reynolds, 2001;Sipos et al, 2003). Additionally, and also in accord with literature (Kim et al, 2004;Zhang et al, 2004;Wang et al, 2006;Hu et al, 2007) the oxidative status produced by mitochondrial inhibition is prevented by incubation of tissues with NAC. Selected concentrations of mitochondrial poisons, effective to decrease E GSH , also activated CB chemoreceptor cells eliciting the release of neurotransmitters.…”

Section: Discussionsupporting

confidence: 85%

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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Section: Discussionsupporting

confidence: 85%

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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“…Our experiments demonstrate a concentration-dependent effect of Mn on the ΔΨm in cultured astrocytes (Fig 5). Studies by Zhang et al (2004) have shown that high levels of MnCl 2 (1 mM) cause a significant dissipation of the ΔΨm in isolated rat brain mitochondria, consistent with induction of the MPT. Our results are also in agreement with an earlier study by Rama Rao and Norenberg (2004), which found that Mn causes a dissipation of the ΔΨm in a concentration-and time-dependent manner in astrocytes.…”

Section: Discussionmentioning

confidence: 81%

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Yin

Aschner

Santos³

et al. 2008

Brain Research

116

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Chronic exposure to excessive levels of Mn results in a movement disorder termed manganism, which resembles Parkinson's disease (PD). The pathogenic mechanisms underlying this disorder are not fully understood. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity. In the present study, we investigated the effects of Mn on mitochondrial function. Primary astrocyte cultures were prepared from cerebral cortices of one-day-old Sprague-Dawley rats. We have examined the cellular toxicity of Mn and its effects on the phosphorylation of extracellular signalregulated kinase (ERK) and activation of the precursor protein of caspase-3. The potentiometric dye, tetramethylrhodamine ethyl ester (TMRE), was used to assess the effect of Mn on astrocytic mitochondrial inner membrane potential (ΔΨ m ). Our studies show that, in a concentration-dependent manner, Mn induces significant (p<0.05) activation of astrocyte caspase-3 and phosphorylated extracellular signal-regulated kinase (p-ERK). Mn treatment (1 and 6 hrs) also significantly (p<0.01) dissipates the ΔΨm in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. These results suggest that activations of astrocytic caspase-3 and ERK are involved in Mn-induced neurotoxicity via mitochondrial-dependent pathways.

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“…Other studies (33) also indicated that manganese inhibits Ca 2ϩ efflux from mitochondria, suggesting the possibility that mitochondria are undergoing the MPT following manganese exposure. More recently, Zhang et al (34) have shown that high levels of manganese chloride (1 mM) caused a significant dissipation of the ⌬⌿ m in isolated rat brain mitochondria, consistent with the induction of the MPT.…”

Section: Figmentioning

confidence: 77%

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

Rao¹,

Norenberg

2004

Journal of Biological Chemistry

112

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Manganese is known to cause central nervous system injury leading to parkinsonism and to contribute to the pathogenesis of hepatic encephalopathy. Although mechanisms of manganese neurotoxicity are not completely understood, chronic exposure of various cell types to manganese has shown oxidative stress and mitochondrial energy failure, factors that are often implicated in the induction of the mitochondrial permeability transition (MPT). In this study, we examined whether exposure of cultured neurons and astrocytes to manganese induces the MPT. Cells were treated with manganese acetate (10 -100 M), and the MPT was assessed by changes in the mitochondrial membrane potential and in mitochondrial calcein fluorescence. In astrocytes, manganese caused a dissipation of the mitochondrial membrane potential and decreased the mitochondrial calcein fluorescence in a concentration-and time-dependent manner. These changes were completely blocked by pretreatment with cyclosporin A, consistent with induction of the MPT. On the other hand, similarly treated cultured cortical neurons had a delayed or reduced MPT as compared with astrocytes. The manganese-induced MPT in astrocytes was blocked by pretreatment with antioxidants, suggesting the potential involvement of oxidative stress in this process. Induction of the MPT by manganese and associated mitochondrial dysfunction in astrocytes may represent key mechanisms in manganese neurotoxicity.Manganese is an essential element and an integral component of key enzymes such as glutamine synthetase and mitochondrial superoxide dismutase (Mn-SOD) 1 (1). However, excess deposition of manganese in the central nervous system often leads to neurological abnormalities, including manganism, the symptoms of which (hypokinesis, rigidity, and tremor) resemble Parkinson's disease (2). Manganism is an occupational health problem in workers employed in welding factories, manganese mines, and ferro-alloy plants (3). In addition, the widespread use of the manganese derivative methylcyclopentadienyl manganese as an anti-knock agent in gasoline has evolved into a major environmental issue (4). Further, manganese toxicity has been implicated in the mechanism of hepatic encephalopathy, a neurological condition associated with chronic liver failure (5, 6).The mechanisms of manganese neurotoxicity are not completely understood. Several reports propose that manganese neurotoxicity is mainly associated with mitochondrial dysfunction (7), leading to decreased oxidative phosphorylation (8). Manganese has also been shown to induce oxidative stress (9 -11).Oxidative stress is considered a major factor in the induction of the mitochondrial permeability transition (MPT) (12, 13). The MPT is a Ca ϩ2 -dependent process often associated with various other factors (14). The MPT is characterized by opening of the permeability transition pore in the inner mitochondrial membrane, resulting in increased permeability of this membrane to protons, ions, and other solutes Յ1500 Da. This increased permeability leads to a coll...

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In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain

Cited by 142 publications

References 29 publications

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

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

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

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