Manganese-induced reactive oxygen species: Comparison between Mn+2 and Mn+3

Ali, Syed F.; Duhart, Helen M.; Newport, Glenn D.; Lipe, George W.; Slikker, William

doi:10.1016/1055-8330(95)90023-3

Cited by 119 publications

(76 citation statements)

References 19 publications

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“…A greater effect of Mn(III) than Mn(II) on the expression of TfR mRNA could also promote more cellular uptake of Fe from the extracellular matrix in Mn(III)-treated cultures, bringing about Fe-initiated oxidative stress. The higher cytotoxicity of Mn(III) than Mn(II) has also been reported by other groups (Ali et al, 1995;Archibald and Tyree, 1987;Donaldson et al, 1982). These investigators have reported that the trivalent or higher valence states of Mn may produce the reactive oxidative species, promote the oxidation of catecholamines, and enhance lipid peroxidation.…”

Section: Discussionsupporting

confidence: 50%

Differential Cytotoxicity of Mn(II) and Mn(III): Special Reference to Mitochondrial [Fe-S] Containing Enzymes

Chen

Tsao

Zhao

et al. 2001

Toxicology and Applied Pharmacology

116

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Manganese (Mn)-induced neurodegenerative toxicity has been associated with a distorted iron (Fe) metabolism at both systemic and cellular levels. In the current study, we examined whether the oxidation states of Mn produced differential effects on certain mitochondrial [Fe-S] containing enzymes in vitro. When mitochondrial aconitase, which possesses a [4Fe-4S] cluster, was incubated with either Mn(II) or Mn(III), both Mn species inhibited the activities of aconitase. However, the IC 10 (concentration to cause a 10% enzyme inhibition) for Mn(III) was ninefold lower than that for Mn(II). Following exposure of mitochondrial fractions with Mn(II) or Mn(III), there was a significant inhibition by either Mn species in activities of Complex I whose active site contains five to eight [Fe-S] clusters. The dose-time response curves reveal that Mn(III) was more effective in blocking Complex I activity than Mn(II). Northern blotting was used to examine the expression of mRNAs encoding transferrin receptor (TfR), which is regulated by cytosolic aconitase. Treatment of cultured PC12 cells with Mn(II) and Mn(III) at 100 μM for 3 days resulted in 21 and 58% increases, respectively, in the expression of TfR mRNA. Further studies on cell growth dynamics after exposure to 25-50 μM Mn in culture media demonstrated that the cell numbers were much reduced in Mn(III)-treated groups compared to Mn(II)-treated groups, suggesting that Mn(III) is more effective than Mn(II) in cell killing. In cells exposed to Mn(II) and Mn(III), mitochondrial DNA (mtDNA) was significantly decreased by 24 and 16%, respectively. In contrast, rotenone and MPP+ did not seem to alter mtDNA levels. These in vitro results suggest that Mn(III) species appears to be more cytotoxic than Mn(II) species, possibly due to higher oxidative reactivity and closer radius resemblance to Fe. Keywords manganese; iron; aconitase; Complex I; speciation; transferrin receptor; PC12 cells; mitochondria; mitochondrial DNA; cytotoxicity; Fe-S cluster Chronic manganese (Mn) intoxication in humans causes permanent neurodegenerative damage in the nigrostriatal region, resulting in a syndrome similar to Parkinson's disease (PD;Cook et al., 1974;Mena et al., 1967 Jenner et al., 1992;Sofic et al., 1991;Ye et al., 1996). A recent population study has also established that serum Fe concentrations are significantly reduced in IPD patients compared with controls, suggesting a compartment shift in Fe from blood to tissues, including brain (Logroscino et al., 1997). The role of Fe in etiopathology of IPD has been extensively reviewed by Jenner et al. (1992) and Youdim et al. (1993).Previous studies from this laboratory have established that Mn-induced neurotoxicities appear to be associated with its interaction with Fe at systemic and cellular levels (Zheng et al., 1998Zheng and Zhao, 2001). Following Mn exposure, there is a predominant influx of Fe from the blood into the cerebrospinal fluid (CSF) and from extracellular matrix to intracellular space Zheng and Zhao, 2001 et al., 1983...

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Section: Discussionsupporting

confidence: 50%

Differential Cytotoxicity of Mn(II) and Mn(III): Special Reference to Mitochondrial [Fe-S] Containing Enzymes

Chen

Tsao

Zhao

et al. 2001

Toxicology and Applied Pharmacology

116

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“…Another laboratory showed evidence suggesting that the ATPase complex is inhibited at very low levels of mitochondrial Mn, and that complex I is inhibited only at higher concentrations (Gavin et al, 1999). Although, trivalent Mn is more effective at inhibiting complex I (Archibald and Tyree, 1987;Ali et al, 1995;Chen et al, 2001), the divalent form is by far the predominant species within cells and is largely bound to ATP (Ali et al, 1995;Gunter et al, 2002). Nevertheless, in biological media, Mn of any valence will spontaneously give rise to small amounts of trivalent Mn.…”

Section: Mechanisms Of Mn Neurotoxicity Oxidative Stressmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

224

141

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Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m 3 ) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

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Section: Introductionmentioning

confidence: 99%

“…Both of these manganese species are in the Mn 2+ state, but Mn neurotoxicity has also been observed with Mn 3+ species of Mn, another oxidation state at which this metal can exist (HaMai et al, 2001;Archibald and Tyree, 1987;Ali et al, 1995). Moreover, earlier studies have indicated that Mn 3+ is more toxic to the nervous system, including the basal ganglia (Ali et al, 1995). However, the cellular compartment where most Mn accumulates following excessive exposure are the mitochondria with recent findings indicating that Mn present in the brain mitochondria is primarily in the Mn 2+ state (Gunter et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study

Sistrunk

Ross

Filipov

2007

Environmental Toxicology and Pharmacology

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Following combustion of fuel containing the additive methylcyclopentadienyl-manganesetricarbonyl (MMT), manganese phosphate (MnPO 4 ) and manganese sulfate (MnSO 4 ) are emitted in the atmosphere. Manganese chloride (MnCl 2 ), another Mn 2+ species, is widely used experimentally. Using rat striatal slices, we found that MnPO 4 decreased tissue and media dopamine (DA) and media Dopac (a DA metabolite) levels substantially more than either MnCl 2 or MnSO 4 ; antioxidants were partially protective. Also, both MnCl 2 and MnPO 4 (more potently) oxidized DA and Dopac even in the absence of tissue in the media, suggesting a direct interaction between Mn and DA/Dopac. Because aminochrome is a major oxidation product of DA, we next determined whether MnPO 4 will be more potent in forming aminochrome than MnCl 2 or MnSO 4 which, indeed, was the case. Thus, a potential additional mechanism for the neurotoxic effects of environmentally-relevant forms of Mn, MnPO 4 in particular, is the generation of reactive DA intermediates.

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Manganese-induced reactive oxygen species: Comparison between Mn+2 and Mn+3

Cited by 119 publications

References 19 publications

Differential Cytotoxicity of Mn(II) and Mn(III): Special Reference to Mitochondrial [Fe-S] Containing Enzymes

Differential Cytotoxicity of Mn(II) and Mn(III): Special Reference to Mitochondrial [Fe-S] Containing Enzymes

Manganese neurotoxicity: A focus on the neonate

Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study

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