title: Cytochrome c oxidase and nitric oxide in action: molecular mechanisms and pathophysiological implications.
abstract: BACKGROUND
  The reactions between Complex IV (cytochrome c oxidase, CcOX) and nitric oxide (NO) were described in the early 60's. The perception, however, that NO could be responsible for physiological or pathological effects, including those on mitochondria, lags behind the 80's, when the identity of the endothelial derived relaxing factor (EDRF) and NO synthesis by the NO synthases were discovered. NO controls mitochondrial respiration, and cytotoxic as well as cytoprotective effects have been described. The depression of OXPHOS ATP synthesis has been observed, attributed to the inhibition of mitochondrial Complex I and IV particularly, found responsible of major effects.
  
  
  METHODS
  The review is focused on CcOX and NO with some hints about pathophysiological implications. The reactions of interest are reviewed, with special attention to the molecular mechanisms underlying the effects of NO observed on cytochrome c oxidase, particularly during turnover with oxygen and reductants.
  
  
  CONCLUSIONS
  The NO inhibition of CcOX is rapid and reversible and may occur in competition with oxygen. Inhibition takes place following two pathways leading to formation of either a relatively stable nitrosyl-derivative (CcOX-NO) of the enzyme reduced, or a more labile nitrite-derivative (CcOX-NO(2)(-)) of the enzyme oxidized, and during turnover. The pathway that prevails depends on the turnover conditions and concentration of NO and physiological substrates, cytochrome c and O(2). All evidence suggests that these parameters are crucial in determining the CcOX vs NO reaction pathway prevailing in vivo, with interesting physiological and pathological consequences for cells.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Italy. paolo.sarti@uniroma1.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Sarti
authors.forename: Elena
authors.initials: E
authors.lastname: Forte
authors.forename: Daniela
authors.initials: D
authors.lastname: Mastronicola
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuffrè
authors.forename: Marzia
authors.initials: M
authors.lastname: Arese
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D010100:Oxygen