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- Title
Nitric Oxide and Mitochondrial Complex IV.
- Authors
Sarti, Paolo; Arese, Marzia; Bacchi, Antonella; Barone, Maria Cecilia; Forte, Elena; Mastronicola, Daniela; Brunori, Maurizio; Giuffrè, Alessandro
- Abstract
Micromolar nitric oxide (NO) rapidly (ms) inhibits cytochrome c oxidase in turnover with physiological substrates. Two reaction mechanisms have been identified leading, respectively, to formation of a nitrosyl-[a[sub 3, sup 2+]-NO] or a nitrite-[a[sub 3, sup 3+]-NO[sub 2, sup -]] derivative of the enzyme. In the presence of O[sub 2], the nitrosyl adduct recovers activity slowly, following NO displacement at k'≈0.01 s[sup -1] (37°C); the recovery of the nitrite adduct is much faster. Relevant to pathophysiology, the enzyme does not degrade NO by following the first mechanism, whereas by following the second one it promotes NO oxidation and disposal as nitrite/nitrate. The reaction between NO and cytochrome c oxidase has been investigated at different integration levels of the enzyme, including the in situ state, such as in mouse liver mitochondria or cultured human SY5 Y neuroblastoma cells. The respiratory chain is inhibited by NO, either supplied exogenously or produced endogenously via the NO synthase activation. Inhibition of respiration is reversible, although it remains to be clarified whether reversibility is always full and how it depends on concentration of and time of exposure to NO. Oxygraphic measurements show that cultured cells or isolated state 4 mitochondria exposed to micromolar (or less) NO recover from NO inhibition rapidly, as if the nitrite reaction was predominant. Mitochondria in state 3 display a slightly more persistent inhibition than in state 4, possibly due to a higher accumulation of the nitrosyl adduct. Among a number of parameters that appear to control the switch over between the two mechanisms, the concentration of reductants (reduced cytochrome c) at the cytochrome c oxidase site has been proved to be the most relevant one. Keywords Nitric oxide; respiratory chain; free radical; cytochrome c oxidase; reaction mechanism; mitochondria; cell bioenergetics.
- Subjects
NITRIC oxide; CYTOCHROME c; NITROSYL chloride; PATHOLOGICAL physiology; MITOCHONDRIA; BIOENERGETICS
- Publication
IUBMB Life, 2003, Vol 55, Issue 10/11, p605
- ISSN
1521-6543
- Publication type
Article
- DOI
10.1080/15216540310001628726