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First published online 12 December 2006
doi: 10.1242/jcs.03308

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Cytochrome c oxidase maintains mitochondrial respiration during partial inhibition by nitric oxide

Miriam Palacios-Callender^1,*, Veronica Hollis^1,*, Nanci Frakich¹, Jesús Mateo² and Salvador Moncada^1,

¹ Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, UK
² Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain

Author for correspondence (e-mail: s.moncada{at}ucl.ac.uk)

Accepted 19 October 2006

Nitric oxide (NO), generated endogenously in NO-synthase-transfected cells, increases the reduction of mitochondrial cytochrome c oxidase (CcO) at O₂ concentrations ([O₂]) above those at which it inhibits cell respiration. Thus, in cells respiring to anoxia, the addition of 2.5 µM L-arginine at 70 µM O₂ resulted in reduction of CcO and inhibition of respiration at [O₂] of 64.0±0.8 and 24.8±0.8 µM, respectively. This separation of the two effects of NO is related to electron turnover of the enzyme, because the addition of electron donors resulted in inhibition of respiration at progressively higher [O₂], and to their eventual convergence. Our results indicate that partial inhibition of CcO by NO leads to an accumulation of reduced cytochrome c and, consequently, to an increase in electron flux through the enzyme population not inhibited by NO. Thus, respiration is maintained without compromising the bioenergetic status of the cell. We suggest that this is a physiological mechanism regulated by the flux of electrons in the mitochondria and by the changing ratio of O₂:NO, either during hypoxia or, as a consequence of increases in NO, as a result of cell stress.

Key words: Cytochrome c oxidase, Electron turnover, Mitochondrial respiration, Nitric oxide, Redox state

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