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Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species
Open accessAbstract
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 H 2 O 2 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,α-ketoglutarate supported the highest rate of H 2 O 2 production. In the absence of ADP or in the presence of rotenone, H 2 O 2 production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of α-ketoglutarate. Isolated mitochondrial α-ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H 2 O 2. NAD+inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H 2 O 2 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 H 2 O 2 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.
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Self-citation
Metadata
- Authors
- Starkov, A. A., Fiskum, G., Chinopoulos, C., Lorenzo, B. J., Browne, S. E., Patel, M. S., & Beal, M. F.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-09-08
- Volume
- 24
- Issue
- 36
- Pages
- 7779-7788
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W2147849026
- Cited by
- 688
- References
- 8
- FWCI
- 8.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
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