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(42) MITOCHONDRIAL FUNCTION IN NEURONAL INJURY I.J. Reynolds, J.F. Buckman,
J. Brocard, Y. Han and T.V. Votyakova
A number of recent studies have suggested that glutamate-mediated excitotoxic neuronal injury occurs as a result of excessive accumulation of calcium in mitochondria. We have established that this stimulus can cause ROS generation and mitochondrial depolarization rapidly after the application of glutamate. However, we lack information about the critical events that link glutamate mediated calcium entry to neuronal death. Our current studies are investigating several key components of this process. We have used low affinity calcium indicators to monitor the magnitude of mitochondrial calcium accumulation in association with injurious stimuli, using the uncoupler FCCP to release calcium from the matrix into the cytoplasm. These studies suggest that neuronal injury is associated with matrix calcium accumulation equivalent to several millimolar. We are also investigating the mechanisms by which brain mitochondria generate ROS, and the impact of Dym on this process. Brain mitochondria using succinate as the main substrate generate ROS via a mechanism very sensitive to Dym, such that very small depolarizations prevent ROS generation. While using glutamate and malate as substrates, brain mitochondria do not generate measurable ROS until complex I is inhibited with rotenone, which is also associated with depolarization of Dym. We are also investigating the characteristics of spontaneous alterations in Dym that can be observed in neurons and astrocytes. Thus, there are clearly several distinct processes to consider as candidate mechanisms to account for glutamate mediated changes in mitochondrial function that lead to neuronal injury.
For further information contact...Carmen Mannella: carmen@wadsworth.org |
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