Occupational and environmental exposures to manganese (Mn) have long been known to lead to neurological symptoms somewhat similar to those of Parkinson's disease (PD). Furthermore, Mn exposure is recognized as a risk factor for idiopathic PD. With the use of Mn as a gasoline additive, increased use in pesticides, and potential clinical use of a Mn superoxide dismutase mimetic, EUK-8, exposures of the general population to Mn will increase. It is vital that we determine the causes for its neurotoxic effects. In the cells of its target brain tissue, primarily neurons of the globus pallidus and striatum, Mn is sequestered by the mitochondria. The leading hypothesis for Mn-induced damage was through oxidation of important cell and mitochondrial components by the powerful oxidizing agent, Mn3+. However, using XANES spectroscopy, we have shown that Mn3+ does not accumulate in mitochondria or neuron-like cells (PC12 or NT2 cells) because of oxidation of Mn2+. Therefore, either Mn3+ is transported into target cells by a specialized transport system, such as transferrin, or the neuronal damage is caused by Mn2+. Intramito-chondrial Ca2+ is known to activate and control ATP production through binding to a set of intramitochon-drial binding sites involved with oxidative phosphorylation. Since Mn2+ generally binds more strongly to Ca2+ binding sites than Ca2+, we have identified Mn2+ interference with Ca2+ activation of ATP production as a potential cause of Mn- induced damage, particularly to active neurons like those of the basal ganglia. Since this Ca2+-activated ATP production can increase the rate of ATP production several fold, its loss could seriously impact upon the function and vitality of active neurons. Therefore, we have proposed to determine whether Mn3+ can be transported into neuron-like cells or astrocytes via transferrin, using the XANES techniques that we have developed during the past five years, and to determine whether Mn2+ interferes with Ca2+ activation and control of ATP production. We propose to study the effects of Mn2+ at each relevant site of intramitochondrial Ca2+ binding, and at the transporter believed to be responsible for the transport of activating Ca2+ into the mitochondria using specially developed optical techniques.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Rochester
Schools of Dentistry
United States
Zip Code
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

Showing the most recent 10 out of 19 publications