Abstract
The mitochondrial electron transport chain (ETC) creates most of the reactive oxygen species (ROS) produced by the average eukaryotic cell. These ROS, primarily superoxide radical, hydrogen peroxide, and hydroxyl radical, can damage the proteins, phospholipids, and nucleic acids of the mitochondria and the entire cell, though they also play important roles in cell signaling. Addition of ions such as Ca2+ or Mn2+ to mitochondria is known to increase ROS production. Excessive manganese (Mn) uptake by the brain, particularly by the globus pallidus and striatum, can cause signs and symptoms somewhat similar to those of Parkinson’s disease (PD); however, unlike PD, manganese toxicity, or manganism, is characterized pathologically by apoptotic cell death in the globus pallidus (GP). Initial effects of excessive brain Mn2+ include inhibition of ATP production and increased generation of mitochondrial ROS. We do not know the exact pathways that lead from these initial insults to the death of GP cells. However, ATP inhibition and increased ROS have been shown to contribute to the activation of apoptotic processes. ROS increase the probability of induction of the mitochondrial permeability transition (MPT), which causes rapid swelling of the mitochondrial matrix, tearing or leakage of the mitochondrial outer membrane, and release of factors from the mitochondrial intermembrane space which activate apoptosis. It is likely that treatments which ameliorate mitochondrial ROS damage will prove beneficial in minimizing the signs and symptoms of Mn toxicity.
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The authors thank Dr. David Hoffman, Dr. Paul Brookes, and Dr. Roman Eliseev for valuable discussions and Dr. Michael Aschner and Mr. Brent Gerstner for reading and commenting on the manuscript.
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Gunter, T.E., Gavin, C.E., Gunter, K.K. (2012). The Role of Mitochondrial Oxidative Stress and ATP Depletion in the Pathology of Manganese Toxicity. In: Li, Y., Zhang, J. (eds) Metal Ion in Stroke. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9663-3_29
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