Manganese toxicity primarily causes loss of dopamine in the striatum and devastation of the cells of the globus pallidus (GP) associated with the symptoms of rigidity and dystonia. It has often been hypothesized that loss of dopamine (DA) is through oxidation induced by Mn3+ and there is evidence that Mn3+ can oxidize Da, But there is very limited evidence on the amount of Mn3+ present in mitochondria and cells. While oxidation by Mn3+ may explain loss of DA, it does not satisfactory explain the cell loss particularly in the GP. We hypothesize that this cell loss may be mitochondrially linked. Past work has shown that Mn2+ traverses the mitochondrial inner membrane via the mitochondrial Ca2+ transport mechanisms. Ca2+ increases Mn2+ uptake via the uniporter and intramitochondrial Mn2 inhibits Ca2+ efflux via both the Na+dependent and Na+- independent efflux mechanisms. In the presence of physiological amounts of Mg2+ in the external medium, Mn2 can even increase Ca2 influx via the uniporter by displacing Mg2+ from the uniporter activation site. These Mn2+ effects increase the amount of Ca2+ present within the mitochondrial matrix. Genrally, increasing matrix Ca2+ has been found to increase the probability of inducing the mitochondrial permeability transition (MPT), and opening of the MPT leads to mitochondrial swelling, which can cause tearing of the outer membrane, loss of cytochrome c from the intermembrane space and apoptosis. Mn is not transported via the very active Na+- dependent efflux mechanism but only by the very slow Na+- independent mechanism in brain explaining its retention in brain mitochondria. We propose; 1) to study Mn speciation in mitochondria and cells using the shift in position of the Mn absorption edge with oxidation state to distinguish and quantify the oxidation states of Mn. This latter approach is called X-ray near edge structure (XANES) spectroscopy. 2) to evaluate the hypothesis of mitochondrially-linked cell killing by Mn, outlined above, and 3) to investigate Mn2+ effects on a recently discovered mechanism of mitochondrial Ca2+ uptake, the RaM, which could play an important role in control of cellular metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010041-04
Application #
6641160
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Humble, Michael C
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$319,000
Indirect Cost
Name
University of Rochester
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Gunter, Thomas E; Gerstner, Brent; Gunter, Karlene K et al. (2013) Manganese transport via the transferrin mechanism. Neurotoxicology 34:118-27
Gunter, Thomas E; Gerstner, Brent; Lester, Tobias et al. (2010) An analysis of the effects of Mn2+ on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays. Toxicol Appl Pharmacol 249:65-75
Eliseev, Roman A; Malecki, Jonathan; Lester, Tobias et al. (2009) Cyclophilin D interacts with Bcl2 and exerts an anti-apoptotic effect. J Biol Chem 284:9692-9
Vanwinkle, Beth A; de Mesy Bentley, Karen L; Malecki, Jonathan M et al. (2009) Nanoparticle (NP) uptake by type I alveolar epithelial cells and their oxidant stress response. Nanotoxicology 3:307-318
Gunter, Thomas E; Gavin, Claire E; Gunter, Karlene K (2009) The case for manganese interaction with mitochondria. Neurotoxicology 30:727-9
Gunter, Thomas E; Sheu, Shey-Shing (2009) Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms. Biochim Biophys Acta 1787:1291-308
Eliseev, Roman A; Filippov, Gleb; Velos, Janice et al. (2007) Role of cyclophilin D in the resistance of brain mitochondria to the permeability transition. Neurobiol Aging 28:1532-42
Gunter, Karlene K; Aschner, Michael; Miller, Lisa M et al. (2006) Determining the oxidation states of manganese in NT2 cells and cultured astrocytes. Neurobiol Aging 27:1816-26
Gunter, Thomas E; Gavin, Claire E; Aschner, Michael et al. (2006) Speciation of manganese in cells and mitochondria: a search for the proximal cause of manganese neurotoxicity. Neurotoxicology 27:765-76
Gunter, Karlene K; Aschner, Michael; Miller, Lisa M et al. (2005) Determining the oxidation states of manganese in PC12 and nerve growth factor-induced PC12 cells. Free Radic Biol Med 39:164-81

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