Journal of Biological Chemistry
Volume 279, Issue 17, 23 April 2004, Pages 17197-17204
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Metabolism and Bioenergetics
Opening of the Mitochondrial Permeability Transition Pore Induces Reactive Oxygen Species Production at the Level of the Respiratory Chain Complex I*

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We have investigated the consequences of permeability transition pore (PTP) opening on the rate of production of reactive oxygen species in isolated rat liver mitochondria. We found that PTP opening fully inhibited H2O2 production when mitochondria were energized both with complex I or II substrates. Because PTP opening led to mitochondrial pyridine nucleotide depletion, H2O2 production was measured again in the presence of various amounts of NADH. PTP opening-induced H2O2 production began when NADH concentration was higher than 50 μm and reached a maximum at over 300 μm. At such concentrations of NADH, the maximal H2O2 production was 4-fold higher than that observed when mitochondria were permeabilized with the channel-forming antibiotic alamethicin, indicating that the PTP opening-induced H2O2 production was not due to antioxidant depletion. Moreover, PTP opening decreased rotenone-sensitive NADH ubiquinone reductase activity, whereas it did not affect the NADH FeCN reductase activity. We conclude that PTP opening induces a specific conformational change of complex I that (i) dramatically increases H2O2 production so long as electrons are provided to complex I, and (ii) inhibits the physiological pathway of electrons inside complex I. These data allowed the identification of a novel consequence of permeability transition that may partly account for the mechanism by which PTP opening induces cell death.

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This work was supported by Grants from INSERM, the Ministère de l'Enseignement de la Recherche et de la Technologie, the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer (Comité de la Drôme), and the Région Rhône-Alpes (Programmes Émergence). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.