The Chemical Interplay between Nitric Oxide and Mitochondrial CytochromecOxidase: Reactions, Effectors and Pathophysiology

Abstract

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-NO2 −, 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 c 2+ and O2 concentration. High cytochrome c 2+, 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 ΔΨ, 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.

Nitric oxide inhibits the mitochondrial carnitine/acylcarnitine carrier through reversible S -nitrosylation of cysteine 136

“…Our present findings agree well with a stepwise process previously described, leading from the physiological inhibition of Complex IV at low NO concentrations, to the pathophysiological inhibition of Complex I at higher NO concentrations [26]. Inhibition of CACT would have a synergistic effect with Complex I, thus being useful in the cytoprotection exerted by inhibition of the enzyme [33,45]. In addition, the unidirectional function of CACT, that plays the role of providing mitochondria with cytosolically synthesized carnitine [22,46], is also strongly inhibited by NO.…”

“…On this basis, S-nitrosylation of CACT may have importance under specific conditions in which mitochondrial oxidation of fatty acids must be slowed down to avoid CoA trapping by acetyl-CoA. Such conditions may occur under impairment of respiratory chain activity which can be caused, among other conditions, by increased intramitochondrial NO level and inhibition of Complex I [25,33]. Interestingly, inhibition of CACT by NO exhibits similar properties of Complex I, i.e., sensitivity to relatively high concentration of NO and slow reaction rate; CACT seems more sensitive to reaction with NO since maximal inhibition is reached at incubation time and GSNO concentration slightly lower than those required by Complex I [34].…”

New Evidence for Cross Talk between Melatonin and Mitochondria Mediated by a Circadian-Compatible Interaction with Nitric Oxide

“…On the same time scale, the cell O 2 consumption is lowered, with predictable outcomes on the mitochondrial bioenergetics [39,40]. The cell oxidative phosphorylation and the glycolytic efficiency have been, therefore, evaluated, measuring the concentration of ATP and lactate.…”

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

“…In fact, one of the earliest studies on NO-related species and mitochondria concerns direct binding to complex IV (cytochrome c oxidase) [77]. More recent studies have suggested that NO-related species may undergo at least two different reactions with cytochrome c oxidase [78]. NO rapidly inhibits cytochrome oxidase at nanomolar levels, suggesting that cytochrome oxidase is a potential (patho)physiologically-relevant target of NO [79].…”