Nitric Oxide

Nitric Oxide (Second Edition)

Biology and Pathobiology
2010, Pages 441-482
Nitric Oxide

Chapter 13 - The Regulation of Cell Energetics and Mitochondrial Signaling by Nitric Oxide

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This chapter reviews nitric oxide (NO) mitochondrial metabolism, following the classical concept of biochemical metabolism that comprises NO production, NO utilization, NO steady-state concentration, and NO-mediated regulation of mitochondrial functions. Mammalian tissues and cells exhibit more than one nitric oxide synthase (NOS), and this is understood as the expression and activity of the genomic NOS: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). The current view is that mammalian cells have two membrane-bound NOS, one located in mitochondria and named mitochondrial nitric oxide synthase (mtNOS) and the other located in the membranes of the endoplasmic or sarcoplasmic reticulum, usually of the eNOS type. The recognition that nitric oxide (NO) acts as a reversible inhibitor of cytochrome oxidase activity competitively with O produced a Copernican revolution in the understanding of the regulation of respiration, especially at low tissue pO. It is now understood that tissue O uptake depends on the O/NO ratio, a concept that has both experimental and mathematical support. Mitochondrial O production, stimulated by NO itself, prevents the inhibition of cytochrome oxidase by NO, providing the reversibility of the regulatory mechanism. The calculated intramitochondrial NO levels (100–360 nM) are in the range of concentrations (80–200 nM NO) that inhibit by 50% cytochrome oxidase activity. Mitochondria have their own source of NO with mtNOS, a transcript of nNOS-α. This is an integral protein of the inner membrane and a voltage-dependent enzyme, and its activity inhibits mitochondrial O uptake. Mitochondrial NO plays a role in cell signaling: decreased mtNOS activity leads to cell proliferation and increased mtNOS activity leads to cell arrest. Overstimulated mtNOS activity and increased NO mitochondrial levels are associated with mitochondrial dysfunction and nitrative and nitrosative stress under a range of pathophysiological conditions.

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Cited by (15)

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    2019, Free Radical Biology and Medicine
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    Despite of the overall changes were more markedly in striatum than in frontal cortex, both cerebral areas from rotenone-treated rats for 60 days exhibit a complex I syndrome [5], similar to the one observed in frontal cortex mitochondria from PD patients [54]. Dysfunction of complex I is usually accompanied by changes in mtNOS activity, increases in H2O2 and ONOO− production rates and oxidative and/or nitrosative damage [5,11,12,18–21]. The decline in complex I and in mtNOS activities is consistent with the two enzymes structurally contiguous and functionally associated [10–13].

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    The mtNOS, same as cytoplasmic NOS isoforms, requires O2, l-arginine, and certain cofactors to produce NO. The apparent O2 KM for heart mtNOS is 36 μM (Alvarez, Valdez, Zaobornyj, & Boveris, 2003), suggesting that under physiological conditions whereby O2 concentration is in the 5–20 μM range (Coburn, Ploegmakers, Gondrie, & Abboud, 1973; Gnaiger, Steinlechner-Maran, Mendez, Eberl, & Margreiter, 1995) the mtNOS activity is O2-limited. To note, the reported KM values for mtNOS indicate a quite low affinity of mtNOS for O2, as compared with other NOS (KM values of eNOS, nNOS, and iNOS are in the range 12–20 μM O2), certainly a point that deserves further research (Boveris, Carreras, & Poderoso, 2009). In this way, the in vivo enzymatic activity of heart mtNOS might be 6–25% of its maximal activity (Boveris & Boveris, 2007).

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    It has been reported by others [38], and also shown in this work, that in myocardial stunning the infarct area is not significant (Fig. 2) and the functional injury is completely reversible (Fig. 1). The mitochondrial dysfunction is properly described as “complex I syndrome” with decreased tissue O2 uptake, decreased malate–glutamate-supported mitochondrial respiration, reduced complex I (NADH-dehydrogenase) activity, increased phospholipid and protein oxidation and protein nitration products, and increased O2•− and H2O2 production rates [39]. Interestingly, high doses of vitamin E were able to restore to normal the age-dependent complex I syndrome in hippocampus and brain cortex [40].

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