Nitric oxide (NO) reacts with Complex I and cytochrome c oxidase (CcOX, Complex IV), inducing detrimental or cytoprotective effects. Two alternative reaction pathways (PWs) have been described whereby NO reacts with CcOX, producing either a relatively labile nitrite-bound derivative (CcOX- , PW1) or a more stable nitrosyl-derivative (CcOX-NO, PW2). The two derivatives are both inhibited, displaying different persistency and O2 competitiveness. In the mitochondrion, during turnover with O2, one pathway prevails over the other one depending on NO, cytochrome and O2 concentration. High cytochrome , and low O2 proved to be crucial in favoring CcOX nitrosylation, whereas under-standard cell-culture conditions formation of the nitrite derivative prevails. All together, these findings suggest that NO can modulate physiologically the mitochondrial respiratory/OXPHOS efficiency, eventually being converted to nitrite by CcOX, without cell detrimental effects. It is worthy to point out that nitrite, far from being a simple oxidation byproduct, represents a source of NO particularly important in view of the NO cell homeostasis, the NO production depends on the NO synthases whose activity is controlled by different stimuli/effectors; relevant to its bioavailability, NO is also produced by recycling cell/body nitrite. Bioenergetic parameters, such as mitochondrial , lactate, and ATP production, have been assayed in several cell lines, in the presence of endogenous or exogenous NO and the evidence collected suggests a crucial interplay between CcOX and NO with important energetic implications. 1. Introduction It is nowadays established that nitrogen monoxide (NO), nitric oxide in the literature, inhibits mitochondrial respiration. The inhibition is induced by the reaction of NO with some of the complexes of the respiratory chain, according to mechanisms studied over more than 20 years. The reaction of NO with Complex III is sluggish [1], whereas the reaction of NO with Complex I and Complex IV, that is, cytochrome oxidase (CcOX), is rapid and to a large extent reversible. Both reactions lead to formation of derivatives responsible of the mitochondrial nitrosative stress observed in different pathophysiological conditions, including main neurodegenerations [2–6]. The functional groups of the mitochondrial complexes reacting with NO include the metals at the catalytic active site of CcOX, namely, the Fe and Cu ions of the heme -CuB site [7, 8]. The inhibition of Complex I results from the reversible S-nitrosation of Cys39 exposed on the surface of the ND3 subunit [9,
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