Succinate Modulation of H2O2 Release at NADH:ubiquinone Oxidoreductase (Complex I) in Brain Mitochondria

Overview

Journal Biochem J

Specialty Biochemistry

Date 2007 May 5

PMID 17477844

Citations 29

Authors

Franco Zoccarato

Lucia Cavallini

Silvia Bortolami

Adolfo Alexandre

Affiliations

Soon will be listed here.

Abstract

Complex I (NADH:ubiquinone oxidoreductase) is responsible for most of the mitochondrial H2O2 release, both during the oxidation of NAD-linked substrates and during succinate oxidation. The much faster succinate-dependent H2O2 production is ascribed to Complex I, being rotenone-sensitive. In the present paper, we report high-affinity succinate-supported H2O2 generation in the absence as well as in the presence of GM (glutamate/malate) (1 or 2 mM of each). In brain mitochondria, their only effect was to increase from 0.35 to 0.5 or to 0.65 mM the succinate concentration evoking the semi-maximal H2O2 release. GM are still oxidized in the presence of succinate, as indicated by the oxygen-consumption rates, which are intermediate between those of GM and of succinate alone when all substrates are present together. This effect is removed by rotenone, showing that it is not due to inhibition of succinate influx. Moreover, alpha-oxoglutarate production from GM, a measure of the activity of Complex I, is decreased, but not stopped, by succinate. It is concluded that succinate-induced H2O2 production occurs under conditions of regular downward electron flow in Complex I. Succinate concentration appears to modulate the rate of H2O2 release, probably by controlling the hydroquinone/quinone ratio.

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References

Turrens J, Boveris A . Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J. 1980; 191(2):421-7. PMC: 1162232. DOI: 10.1042/bj1910421. View

McCormack J, Denton R . The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem J. 1979; 180(3):533-44. PMC: 1161091. DOI: 10.1042/bj1800533. View

Sato K, Kashiwaya Y, Keon C, Tsuchiya N, King M, Radda G . Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995; 9(8):651-8. DOI: 10.1096/fasebj.9.8.7768357. View

Hansford R, Hogue B, Mildaziene V . Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J Bioenerg Biomembr. 1997; 29(1):89-95. DOI: 10.1023/a:1022420007908. View

Korshunov S, Skulachev V, Starkov A . High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 1997; 416(1):15-8. DOI: 10.1016/s0014-5793(97)01159-9. View

Melov S, Coskun P, Patel M, Tuinstra R, Cottrell B, Jun A . Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc Natl Acad Sci U S A. 1999; 96(3):846-51. PMC: 15313. DOI: 10.1073/pnas.96.3.846. View

Antunes F, Boveris A, Cadenas E . On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide. Proc Natl Acad Sci U S A. 2004; 101(48):16774-9. PMC: 534717. DOI: 10.1073/pnas.0405368101. View

Zoccarato F, Toscano P, Alexandre A . Dopamine-derived dopaminochrome promotes H(2)O(2) release at mitochondrial complex I: stimulation by rotenone, control by Ca(2+), and relevance to Parkinson disease. J Biol Chem. 2005; 280(16):15587-94. DOI: 10.1074/jbc.M500657200. View

Schriner S, Linford N, Martin G, Treuting P, Ogburn C, Emond M . Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005; 308(5730):1909-11. DOI: 10.1126/science.1106653. View

10.

Mason M, Nicholls P, Wilson M, Cooper C . Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase. Proc Natl Acad Sci U S A. 2006; 103(3):708-13. PMC: 1334642. DOI: 10.1073/pnas.0506562103. View

11.

Allen R, Tresini M . Oxidative stress and gene regulation. Free Radic Biol Med. 2000; 28(3):463-99. DOI: 10.1016/s0891-5849(99)00242-7. View

12.

Cadenas E, Davies K . Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000; 29(3-4):222-30. DOI: 10.1016/s0891-5849(00)00317-8. View

13.

Votyakova T, Reynolds I . DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J Neurochem. 2001; 79(2):266-77. DOI: 10.1046/j.1471-4159.2001.00548.x. View

14.

Liu Y, Fiskum G, Schubert D . Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem. 2002; 80(5):780-7. DOI: 10.1046/j.0022-3042.2002.00744.x. View

15.

St-Pierre J, Buckingham J, Roebuck S, Brand M . Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem. 2002; 277(47):44784-90. DOI: 10.1074/jbc.M207217200. View

16.

Kushnareva Y, Murphy A, Andreyev A . Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J. 2002; 368(Pt 2):545-53. PMC: 1222999. DOI: 10.1042/BJ20021121. View

17.

Han D, Canali R, Rettori D, Kaplowitz N . Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria. Mol Pharmacol. 2003; 64(5):1136-44. DOI: 10.1124/mol.64.5.1136. View

18.

Zoccarato F, Cavallini L, Alexandre A . Respiration-dependent removal of exogenous H2O2 in brain mitochondria: inhibition by Ca2+. J Biol Chem. 2003; 279(6):4166-74. DOI: 10.1074/jbc.M308143200. View

19.

Lambert A, Brand M . Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem J. 2004; 382(Pt 2):511-7. PMC: 1133807. DOI: 10.1042/BJ20040485. View

20.

Lambert A, Brand M . Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem. 2004; 279(38):39414-20. DOI: 10.1074/jbc.M406576200. View