Mitochondrial Role in Manganese Toxicity

University Of Rochester, Rochester NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]