Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity

Gunter, Thomas E.; Gavin, Claire E.; Aschner, Michael; Gunter, Karlene K.

doi:10.1016/j.neuro.2006.05.002

Cited by 165 publications

(124 citation statements)

References 82 publications

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“…Divalent metal transporter (DMT1) is a component of the endosome and functions to acidify the endosome to allow for release of Tf bound metal and then functions to pump the metal into the cytosol. Presumed is that Mn also is released from Tf-Mn complexes by the same mechanism Gunter et al, 2006) however more studies are needed. This mechanism was elucidated in reticulocytes where TfR is abundant and Tf-Fe complexes (and perhaps Tf-Mn complexes) were able to enter cells but the metal could not be released into the cytosol (Garrick et al, 1993).…”

Section: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 99%

“…found no evidence of stabilization of Mn 3+ complexes in human neuroteratocarcinoma (NT2) cells and primarly rat astrocyte cultures or in nerve growth factor treated PC12 cells . The cause of manganese neurotoxicity is suggested to by due to Mn 2+ inhibition of Ca 2+ activation and control of ATP production (Gunter et al, 2006).…”

Section: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 99%

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Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

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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: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 99%

Section: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

Self Cite

224

141

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“…Only a method of analyzing speciation in situ, using live cells and intact isolated organelles, can provide the required information. X-ray spectroscopic techniques can measure the amounts and distribution of metal ions such as Mn 2þ in cells (17), and give the oxidation state(s) of Mn as well as some information about speciation (18). Herein we show that it is possible to probe Mn 2þ speciation in intact, viable cells through measurements of 1 H and 31 P pulsed electron-nuclear double resonance (ENDOR) (19) signal intensities for intracellular Mn 2þ .…”

mentioning

confidence: 92%

Probing in vivo Mn²⁺speciation and oxidative stress resistance in yeast cells with electron-nuclear double resonance spectroscopy

McNaughton

Reddi

Clement

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

116

143

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Manganese is an essential transition metal that, among other functions, can act independently of proteins to either defend against or promote oxidative stress and disease. The majority of cellular manganese exists as low molecular-weight Mn 2+ complexes, and the balance between opposing “essential” and “toxic” roles is thought to be governed by the nature of the ligands coordinating Mn 2+ . Until now, it has been impossible to determine manganese speciation within intact, viable cells, but we here report that this speciation can be probed through measurements of 1 H and 31 P electron-nuclear double resonance (ENDOR) signal intensities for intracellular Mn 2+ . Application of this approach to yeast ( Saccharomyces cerevisiae ) cells, and two pairs of yeast mutants genetically engineered to enhance or suppress the accumulation of manganese or phosphates, supports an in vivo role for the orthophosphate complex of Mn 2+ in resistance to oxidative stress, thereby corroborating in vitro studies that demonstrated superoxide dismutase activity for this species.

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“…Mitochondria are intracellular target for Mn toxicity (Gunter et al, 2006;Milatovic et al, 2007;Rama Rao et al, 2007). Intracellular Mn 2+ is sequestered by mitochondria via the Ca 2+ uniporter (Mela and Chance, 1968;Gunter et al, 1975;Gavin et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Mn 2+ can be oxidized to the strong pro-oxidizing agent, Mn 3+ , followed by oxidation of important cell components by Mn 3+ (Archibald and Tyree, 1987;Donaldson, 1987); these reactions take place within the mitochondrial matrix. The formation and accumulation of a redox-active Mn 3+ complex in brain mitochondria from oxidation of Mn 2+ result in Mn toxicity (Gunter et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Yin

Aschner

Santos³

et al. 2008

Brain Research

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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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Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity

Cited by 165 publications

References 82 publications

Manganese neurotoxicity: A focus on the neonate

Manganese neurotoxicity: A focus on the neonate

Probing in vivo Mn²⁺speciation and oxidative stress resistance in yeast cells with electron-nuclear double resonance spectroscopy

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

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Speciation of manganese in cells and mitochondria: A search for the proximal cause of manganese neurotoxicity

Cited by 165 publications

References 82 publications

Manganese neurotoxicity: A focus on the neonate

Manganese neurotoxicity: A focus on the neonate

Probing in vivo Mn2+speciation and oxidative stress resistance in yeast cells with electron-nuclear double resonance spectroscopy

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

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Probing in vivo Mn²⁺speciation and oxidative stress resistance in yeast cells with electron-nuclear double resonance spectroscopy