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SPECIAL SECTION ON MITOCHONDRIAL MODELING AND FUNCTION

Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice

¹Carolinas Neuromuscular/ALS-MDA Center, Carolinas Medical Center, Charlotte, North Carolina; and ²Center for Neurodegenerative Disease, and ³Free Radicals in Medicine Core, Division of Cardiology, Emory University, Atlanta, Georgia

Submitted 24 April 2006 ; accepted in final form 11 October 2006

In animal models of neurodegenerative diseases pathological changes vary with the type of organ and species of the animals. We studied differences in the mitochondrial permeability transition (mPT) and reactive oxygen species (ROS) generation in the liver (LM) and brain (BM) of Sprague-Dawley rats and C57Bl mice. In the presence of ADP mouse LM and rat LM required three times less Ca²⁺ to initiate mPT than the corresponding BM. Mouse LM and BM sequestered 70% and 50% more Ca²⁺ phosphate than the rat LM and BM. MBM generated 50% more ROS with glutamate than the RBM, but not with succinate. With the NAD substrates, generation of ROS do not depend on the energy state of the BM. Organization of the respiratory complexes into the respirasome is a possible mechanism to prevent ROS generation in the BM. With BM oxidizing succinate, 80% of ROS generation was energy dependent. Induction of mPT does not affect ROS generation with NAD substrates and inhibit with succinate as a substrate. The relative insensitivity of the liver to systemic insults is associated with its high regenerative capacity. Neuronal cells with low regenerative capacity and a long life span protect themselves by minimizing ROS generation and by the ability to withstand very large Ca²⁺ insults. We suggest that additional factors, such as oxidative stress, are required to initiate neurodegeneration. Thus the observed differences in the Ca²⁺-induced mPT and ROS generation may underlie both the organ-specific and species-specific variability in the animal models of neurodegenerative diseases.

permeability transition; reactive oxygen species generation; interspecies difference