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Medientyp:
E-Artikel
Titel:
Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species
Beteiligte:
Starkov, Anatoly A.;
Fiskum, Gary;
Chinopoulos, Christos;
Lorenzo, Beverly J.;
Browne, Susan E.;
Patel, Mulchand S.;
Beal, M. Flint
Erschienen:
Society for Neuroscience, 2004
Erschienen in:
The Journal of Neuroscience, 24 (2004) 36, Seite 7779-7788
Sprache:
Englisch
DOI:
10.1523/jneurosci.1899-04.2004
ISSN:
0270-6474;
1529-2401
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>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<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>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<jats:italic>p</jats:italic>-trifluoromethoxyphenylhydrazone,α-ketoglutarate supported the highest rate of H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>production. In the absence of ADP or in the presence of rotenone, H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>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<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>. NAD<jats:sup>+</jats:sup>inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>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<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>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.</jats:p>