Cytochrome c oxidase maintains mitochondrial respiration during partial inhibition by nitric oxide.
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 microM L-arginine at 70 microM O2 resulted in reduction of CcO and inhibition of respiration at [O2] of 64.0+/-0.8 and 24.8+/-0.8 microM, 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.
Palacios-Callender
Miriam
M
Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Hollis
Veronica
V
Frakich
Nanci
N
Mateo
Jesús
J
Moncada
Salvador
S
D001120:Arginine / Q000378:metabolism / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D045264:Cytochromes a / Q000378:metabolism; D045266:Cytochromes a3 / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D003574:Cytochrome c Group; D045266:Cytochromes a3; C435384:cytochrome caa(3); D009569:Nitric Oxide; D045264:Cytochromes a; D001120:Arginine; D019001:Nitric Oxide Synthase; D003576:Electron Transport Complex IV; D010100:Oxygen