Nitrite–nitric oxide control of mitochondrial respiration at the frontier of anoxia

Abstract

Actively respiring animal and plant tissues experience hypoxia because of mitochondrial O(2) consumption. Controlling oxygen balance is a critical issue that involves in mammals hypoxia-inducible factor (HIF) mediated transcriptional regulation, cytochrome oxidase (COX) subunit adjustment and nitric oxide (NO) as a mediator in vasodilatation and oxygen homeostasis. In plants, NO, mainly derived from nitrite, is also an important signalling molecule. We describe here a mechanism by which mitochondrial respiration is adjusted to prevent a tissue to reach anoxia. During pea seed germination, the internal atmosphere was strongly hypoxic due to very active mitochondrial respiration. There was no sign of fermentation, suggesting a down-regulation of O(2) consumption near anoxia. Mitochondria were found to finely regulate their surrounding O(2) level through a nitrite-dependent NO production, which was ascertained using electron paramagnetic resonance (EPR) spin trapping of NO within membranes. At low O(2), nitrite is reduced into NO, likely at complex III, and in turn reversibly inhibits COX, provoking a rise to a higher steady state level of oxygen. Since NO can be re-oxidized into nitrite chemically or by COX, a nitrite-NO pool is maintained, preventing mitochondrial anoxia. Such an evolutionarily conserved mechanism should have an important role for oxygen homeostasis in tissues undergoing hypoxia.

Tissue Processing of Nitrite in Hypoxia

“…Our observation that rates of NO 2 Ϫ conversion to NO correlate robustly with maximal mitochondrial respiratory capacity accords with the hypothesis that tissue oxygen demand and ambient oxygen concentration are operationally related through NO 2 Ϫ -dependent NO formation by, or more provocatively for, the ETC (12,34,35). This link between NO 2 Ϫ -dependent NO formation and oxidative intermediary metabolism is further underlined by the notable exception of renal tissue, the renal medulla relying largely on anaerobic metabolism (30).…”

“…Based on the evidence presented herein, it is tempting to speculate that conversion of NO 2 Ϫ to NO is part of a conserved regulatory mechanism that acutely matches oxygen homeostasis to intermediary metabolism (37). As well acting directly on mitochondria (12,35), the resulting nitrosation of master transcription factors such as HIF-1␣ may have a profound impact on the cellular metabolic milieu (39). Different tissue compartments might affect their oxygen-sensing through the common path of NO 2 Ϫ conversion to NO.…”

“…The resulting NO then acts to modify mitochondrial function and the cellular metabolic and transcriptional milieu. This hypothetical paradigm represents a tuning mechanism through which eukaryotic cells might optimize their use of oxygen and carbon units for maximally efficient energy provision (2,33,35). Whether NO 2 Ϫ is indeed involved in such processes and whether there are differences in bioactivity between endogenous and exogenous NO 2 Ϫ will require further investigation.…”

Effects of cadmium exposure and intermittent anoxia on nitric oxide metabolism in eastern oysters,Crassostrea virginica

“…Recent studies in mammals demonstrated that NO is involved in regulation of aerobic metabolism (Brown, 1999;Brown, 2007), as well as in oxygen sensing and regulation of anaerobic energy production during oxygen-deficient states such as hypoxia and ischemia (Berchner-Pfannschmidt et al, 2007;Benamar et al, 2008). Mitochondria appear to be a central hub of NO-dependent regulation of bioenergetics.…”

Nitrogen metabolism in plants under low oxygen stress

“…Based on experiments performed on isolated plant mitochondria, it was proposed that nitrite is the acceptor of electrons generated by the oxidation of NAD(P)H by the Ca 2 + -sensitive NAD(P)H dehydrogenases located at the inner mitochondrial membrane surface involving Complex III (ubiquinone:cytochrome c reductase) or COX (complex IV) of the ETC. Thus, when NO is produced it contributes to ATP synthesis as the result of proton pumping at the sites of complex III or COX (Stoimenova et al 2007;Planchet et al 2005;Gupta and Igamberdiev 2011;Igamberdiev and Hill 2009;Igamberdiev et al 2010;Benamar et al 2008;Jacoby et al 2012). This process called nitrite-NO respiration (NNR) necessitates the transport of nitrite from the cytosol into the mitochondrial matrix through a presently unknown transporter (Horchani et al 2011) (Fig.…”