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The Journal of Neuroscience, September 8, 2004, 24(36):7779-7788; doi:10.1523/JNEUROSCI.1899-04.2004

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Neurobiology of Disease
Mitochondrial -Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

Anatoly A. Starkov,¹ Gary Fiskum,² Christos Chinopoulos,² Beverly J. Lorenzo,¹ Susan E. Browne,¹ Mulchand S. Patel,³ and M. Flint Beal¹

¹Department of Neurology and Neuroscience, Weill Medical College, Cornell University, New York, New York 10021, ²Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland 21202, and ³Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214

Mitochondria-produced reactive oxygen species (ROS) are thought to contribute to cell death caused by a multitude of pathological conditions. The molecular sites of mitochondrial ROS production are not well established but are generally thought to be located in complex I and complex III of the electron transport chain. We measured H₂O₂ production, respiration, and NADPH reduction level in rat brain mitochondria oxidizing a variety of respiratory substrates. Under conditions of maximum respiration induced with either ADP or carbonyl cyanide p-trifluoromethoxyphenylhydrazone,-ketoglutarate supported the highest rate of H₂O₂ production. In the absence of ADP or in the presence of rotenone, H₂O₂ production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of -ketoglutarate. Isolated mitochondrial -ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H₂O₂. NAD⁺ inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H₂O₂ production by brain mitochondria isolated from heterozygous knock-out mice deficient in dihydrolipoyl dehydrogenase (Dld). Although this enzyme is a part of both KGDHC and PDHC, there was greater impairment of KGDHC activity in Dld-deficient mitochondria. These mitochondria also produced significantly less H₂O₂ than mitochondria isolated from their littermate wild-type mice. The data strongly indicate that KGDHC is a primary site of ROS production in normally functioning mitochondria.

Key words: mitochondria; reactive oxygen species; lipoamide dehydrogenase; ketoglutarate dehydrogenase; Parkinson; Alzheimer

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Received May 15, 2004; revised July 14, 2004; accepted July 18, 2004.

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