Cytochrome c oxidase and nitric oxide in action: Molecular mechanisms and pathophysiological implications

• Published in: Biochimica et biophysica acta 2012-04, Vol.1817 (4), p.610-619
• Main Authors: Sarti, Paolo, Forte, Elena, Mastronicola, Daniela, Giuffrè, Alessandro, Arese, Marzia
• Format: Article
• Language: English
• Subjects: adenosine triphosphate; Animals; Biochemistry, Molecular Biology; Cell Respiration; Cell Respiration - physiology; cytochrome c; cytochrome-c oxidase; Cytochromes c; Cytochromes c - metabolism; cytotoxicity; Electron transfer; Electron Transport Complex IV; Electron Transport Complex IV - metabolism; Enzyme inhibition; Hemeproteins; Humans; Life Sciences; Mitochondria; Models, Biological; Nitric Oxide; Nitric Oxide - metabolism; nitric oxide synthase; Oxidation-Reduction; Oxygen; Oxygen - metabolism; Radical chemistry; reducing agents; Respiratory chain; Signal Transduction; Signal Transduction - physiology
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/j.bbabio.2011.09.002

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. 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. 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-NO2−) 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 O2. 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. This article is part of a Special Issue entitled: Respiratory Oxidases. ► Nitric oxide reacts with the metals of the binuclear site of cytochrome c oxidase which is inhibited. ► A nitrosyl-derivative (CcOX-NO) or a nitrite-derivative (CcOX-NO2−) can be formed. ► Persistence of inhibition depends on the prevailing mechanism of reaction. ► Substrates availability, O2 and cytochrome c2+, and the NO concentration control the mechanism. ► Inhibition is O2-competitive only if CcOX nitrosylation occurs.