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J. Biol. Chem., Vol. 280, Issue 51, 42026-42035, December 23, 2005

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Rotenone Model of Parkinson Disease

MULTIPLE BRAIN MITOCHONDRIA DYSFUNCTIONS AFTER SHORT TERM SYSTEMIC ROTENONE INTOXICATION^*

Alexander Panov1, Sergey Dikalov, Natalia Shalbuyeva¶, Georgia Taylor¶, Todd Sherer¶, and J. Timothy Greenamyre¶

From the Carolinas Neuromuscular/ALS-MDA Center, Carolinas Medical Center, Charlotte, North Carolina 28203 and the Free Radicals in Medicine Core, Division of Cardiology, ^¶Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322

Chronic infusion of rotenone (Rot) to Lewis rats reproduces many features of Parkinson disease. Rot (3 mg/kg/day) was infused subcutaneously to male Lewis rats for 6 days using Alzet minipumps. Control rats received the vehicle only. Presence of 0.1% bovine serum albumin during the isolation procedure completely removed rotenone bound to the mitochondria. Therefore all functional changes observed were aftereffects of rotenone toxicity in vivo. In Rot rat brain mitochondria (Rot-RBM) there was a 30-40% inhibition of respiration in State 3 and State 3U with Complex I (Co-I) substrates and succinate. Rot did not affect the State 4 of RBM and rat liver mitochondria (RLM). However, Rot-RBM required two times less Ca²⁺ to initiate permeability transition (mPT). There was a 2-fold increase in or H₂O₂ generation in Rot-RBM oxidizing glutamate. Rot infusion affected RLM little. Our results show that in RBM, the major site of reactive oxygen species generation with glutamate or succinate is Co-I. We also found that Co-II generates substantial amounts of reactive oxygen species that increased 2-fold in the Rot-RBM. Our data suggest that the primary mechanism of the Rot toxic effect on RBM consists in a significant increase of generation that causes damage to Co-I and Co-II, presumably at the level of 4Fe-4S clusters. Decreased respiratory activity diminishes resistance of RBM to Ca²⁺ and thus increases probability of mPT and apoptotic cell death. We suggest that the damage to Co-I and Co-II shifts generation from the CoQ₁₀ sites to more proximal sites, such as flavines, and makes it independent of the RBM functional state.

Received for publication, August 5, 2005 , and in revised form, October 20, 2005.

^* This work was supported by National Institutes of Health NIEHS Grant ES012068 and a grant from the Picower Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1000 Blythe Blvd., Charlotte, NC 28203. Tel.: 704-355-5902; Fax: 704-446-6255; E-mail: alexander.panov{at}carolinashealthcare.org.

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