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Determining the oxidation states of manganese in PC12 and nerve growth factor-induced PC12 cells
Karlene K Gunter1, Michael Aschner, Lisa M Miller
1Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, 575 Elmwood Avenue, Rochester, NY 14642, USA.
Abstract:
Excessive brain Mn can produce toxicity with symptoms resembling parkinsonism. This syndrome, called "manganism," correlates with loss of dopamine in the striatum and cell death in the striatum and globus pallidus. A common hypothesis is that cell damage in Mn toxicity is caused by oxidation of important cell components by Mn3+. Determination of the amount of Mn3+ present, under a range of conditions, in neuronal cells and brain mitochondria represents an important step in evaluating the "damage through oxidation by Mn3+ hypothesis." In an earlier paper we used X-ray absorption near-edge structure (XANES) spectroscopy to determine the amount of Mn2+ and Mn3+ in brain mitochondria under a range of conditions. Here we extend the study to investigate the evidence for formation of Mn3+ through oxidation of Mn2+ by ROS in PC12 cells and in PC12 cells induced with nerve growth factor (NGF) to display a phenotype more like that of neurons. Although the results suggest that very small amounts of Mn3+ might be present at low Mn levels, probably in Mn superoxide dismutase, Mn3+ is not stabilized by complex formation in these cells and therefore does not accumulate to detectable amounts.
Insights
Manganese (Mn) toxicity causes parkinsonism-like symptoms. This study found that while small amounts of Mn3+ may exist in cells, it does not accumulate to detectable levels, challenging the oxidation damage hypothesis.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Excessive manganese (Mn) in the brain causes manganism, a syndrome resembling parkinsonism.
- Manganism is linked to dopamine loss and cell death in brain regions like the striatum and globus pallidus.
- A leading hypothesis suggests Mn3+ oxidizes cellular components, causing damage.
Purpose of the Study:
- To investigate the formation and stabilization of Mn3+ in neuronal cells (PC12) and NGF-induced PC12 cells.
- To evaluate the role of reactive oxygen species (ROS) in oxidizing Mn2+ to Mn3+ within these cells.
- To assess the validity of the
- damage through oxidation by Mn3+ hypothesis.
Main Methods:
- X-ray absorption near-edge structure (XANES) spectroscopy was employed.
- The study extended previous work on brain mitochondria to PC12 cells.
- PC12 cells were induced with nerve growth factor (NGF) to mimic neuronal phenotypes.
Main Results:
- Very small amounts of Mn3+ were detected at low manganese (Mn) levels, likely within Mn superoxide dismutase.
- Mn3+ was not stabilized by complex formation in the studied cells.
- Mn3+ did not accumulate to detectable amounts in PC12 cells, even when differentiated.
Conclusions:
- The hypothesis that cell damage in manganese toxicity is caused by oxidation by Mn3+ is not supported by these findings.
- Manganese toxicity may not directly involve the accumulation of significant amounts of Mn3+ in neuronal cells.
- Further research is needed to understand the precise mechanisms of manganese neurotoxicity.
