Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

By A. Starkov, G. Fiskum, C. Chinopoulos, Beverl J. Lorenzo, S. Browne, M. Patel, M. Beal. Journal of Neuroscience, 2004

611 citations recorded by the source corpus.

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,α-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 α-ketoglutarate. Isolated mitochondrial α-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.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c078516a35d8b0cf104e0dc895c388568c565ee4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. J. Fiedor
2. M. Murphy
3. K. Burda

In Cancer Research

1. M. Murphy
2. S. Dikalov

In Molecular Biology

1. S. Dikalov
2. M. Brand
3. M. Murphy
4. J. Fiedor
5. M. Ogun
6. C. Giorgi
7. P. Pinton
8. K. Burda

Citations in the corpus

• Crosstalk between mitochondria and NADPH oxidases (2011, background): “Other sources of mitochondrial O2 may include α-ketoglutarate dehydrogenase, pyruvate dehydrogenase [32], glycerol-3phosphate dehydrogenase, fatty acid β-oxidation [33], and complex III [34,35].”
• The sites and topology of mitochondrial superoxide production (2010, background): “, 2005), including 2- oxoglutarate and pyruvate dehydrogenases (Chinta et al., 2009; Gazaryan et al., 2002; Starkov et al., 2004; Tretter and Adam-Vizi, 2004) and non-mammalian NADH-Q oxidoreductases (Fang and Beattie, 2003).”
• Mitochondrial proton and electron leaks (2010, background): “Examples include the dihydrolipoamide dehydrogenase-containing FAD-linked pyruvate and α-oxoglutarate dehydrogenase complexes [29], as well as the fl avoenzymes α-glycerophosphate dehydrogenase [30] and the ETFQOR [electron-transferring fl avoprotein:Q (ubiquinone) oxidoreductase] of fatty acid β-ox”
• Biochemistry of Reactive Oxygen and Nitrogen Species (2015, background): “In mitochondria and with isolated enzyme, ROS production from KGDHC was stimulated by a decrease in availability of its natural electron acceptor, NAD+ [51, 52].”
• Selective Neuronal Vulnerability to Oxidative Stress in the Brain (2010, neutral): “Also, elevations in [Ca2+] i can activate mitochondrial dehydrogenases, inhibit complex I, and cause the formation of ROS and, therefore, increase OS (Beal, 1992; Starkov et al., 2004).”
• Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging (2011, background): “Pyruvate dehydrogenase complex (PGDH) localized into mitochondrial matrix contains flavoenzyme dihydrolipoyl dehydrogenase subunits like KGDHC, which are very important ROS sources [38].”
• Potential Role of Carotenoids as Antioxidants in Human Health and Disease (2014, background): “, monoamine oxidase or manganese superoxide dismutase (MnSOD)) are considered as major mitochondrial sources of ROS [34–37].”