Serial review: nitric oxide in mitochondriaPeroxynitrite reactions and formation in mitochondria☆
Introduction
Mitochondria constitute a primary locus for the intracellular formation and reactions of peroxynitrite1, and these interactions are recognized to contribute to the biological and pathological effects of both nitric oxide (•NO) and peroxynitrite. Peroxynitrite can diffuse from extramitochondrial compartments into the mitochondria or be formed intramitochondrially and undergo target molecule reactions with various constituents as well as react with carbon dioxide to yield secondary radicals. Altogether these reactions start one- and two-electron oxidation processes that result in the oxidation, nitration, and/or nitrosation of critical mitochondrial components that can lead to alterations in mitochondrial homeostasis and physiology. The concept of peroxynitrite interactions with mitochondria was originally proposed in 1994 [1]. The hypothesis was triggered by the realization that long-term inhibitory effects on cell respiration exerted by •NO 2, 3 could not be solely explained by the rather limited direct reactions of •NO with mitochondrial components, but was consistent with the participation of •NO-derived secondary species with more robust chemical reactivity, such as peroxynitrite. In addition, as •NO can freely diffuse through membranes and mitochondria is a key intracellular producer of superoxide radical anion (O2•−), the idea of the intramitochondrial formation of peroxynitrite from the rapid •NO reaction with O2•− was elaborated.
While it has been apparent that peroxynitrite formed in extramitochondrial sites can diffuse into and affect mitochondria, the intramitochondrial formation and reactions of peroxynitrite represents a more subtle issue, one that may contribute to explain the decreased biological half-life of •NO under conditions that stimulate mitochondrial O2•− formation, persistent effects of •NO in mitochondrial functions, and mitochondrial signaling of •NO-dependent cell death.
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Peroxynitrite biochemistry and mitochondria
Peroxynitrite anion is formed from the diffusion-controlled reaction between the free radicals •NO and O2•− (k ∼ 1010 M−1s−1). Peroxynitrite anion (ONOO−) is in equilibrium with peroxynitrous acid (ONOOH, pKa = 6.8) and both species are strong oxidizing species in vivo by a variety of mechanisms that involve direct reactions with targets molecules (e.g., thiols, transition metal centers) or by secondary decomposition to free radicals, most notably carbonate (CO3•−) and nitrogen dioxide radicals
Peroxynitrite diffusion and mitochondria
The biological half-life of peroxynitrite in extracellular compartments has been estimated to be in the order of 10 ms, and both peroxynitrite anion and peroxynitrous acid can diffuse across biomembranes 6, 14, 15. Peroxynitrite formed outside mitochondria can diffuse to its interior, although the exact mechanisms remain to be elucidated; on the other hand, peroxynitrite formed intramitochondrially is expected to have a shorter biological half-life (t1/2 ∼ 3–5 ms) due to the large abundance of
In vitro and in vivo evidence supporting the mitochondrial formation/reactions of peroxynitrite
As peroxynitrite in mitochondria is a transient species, the evidence for its intramitochondrial formation mostly derives from (i) its reaction with exogenously added probes, (ii) the oxidative modifications of endogenous molecules (footprinting), and (iii) the SOD-inhibitable consumption and actions of •NO. The existing evidence ranges from observations performed in submitochondrial particles (SMPs) to human tissues, as outlined in Table 1.
Peroxynitrite reactions with electron transport chain components
The effects of peroxynitrite are distinctly different to those of •NO with mitochondrial electron transport chain components [48]. While •NO mainly interacts and inhibits cytochrome c oxidase 29, 48, 49, 50, 51, 52, 53, 54, peroxynitrite reactions with complexes I, II, and V lead to their inactivation 1, 30, 48, 55, 56, 57, 58, 59, 60, by mechanisms that still need to be defined. This may not be an easy task, especially in the case of complexes I and II, as they are multicomponent complexes
Permeability transition pore (PTP) and the pyridine nucleotide-dependent calcium release pathway
Mitochondrial protein complexes that participate in critical mitochondrial/cellular processes such as the permeability transition pore (PTP) opening and the pyridine nucleotide-dependent calcium release pathway, contain inner membrane proteins with critical vicinal thiols that can be readily oxidized by peroxynitrite 77, 78. For the PTP, this protein is the adenine nucleotide translocase (ANT), known to be affected by oxidants including peroxynitrite 79, 80, 81. ANT can form a complex with the
Peroxynitrite interactions with matrix components
A number of matrix components are targets of peroxynitrite or peroxynitrite-derived radicals (Fig. 1). Metalloproteins such as aconitase and Mn-SOD present at 10–20 μM concentrations react with large rate constants with peroxynitrite, while glutathione present at ∼ 5 mM reacts at smaller rates and other compounds such as NADH only react with secondary radicals [6]. The relevant reaction of peroxynitrite with CO2 accounts for approximately half of the fate of peroxynitrite in the matrix and has
Overview of peroxynitrite reactions in mitochondria and their impact in cell homeostasis and death
We can then envision that peroxynitrite can either diffuse into mitochondria or be formed intramitochondrially and rapidly undergo target molecule reactions. All four mitochondrial compartments have interactions with peroxynitrite as VDAC, creatine kinase, ATPase, and aconitase, proteins present in the external membrane, intermembrane, inner membrane, and matrix respectively, are nitrated or oxidized during excess •NO formation (Fig. 3).
Under physiological conditions, low fluxes of
Acknowledgements
This work was supported by grants from Fogarty-National Institutes of Health (USA) and the Howard Hughes Medical Institute (USA) to R.R. C.Q. is partially supported by a fellowship from PEDECIBA (Uruguay). R.R. is a Howard Hughes International Research Scholar.
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Guest Editors: Christoph Richter and Matthias Schweizer
This article is part of a series of reviews on “Nitric Oxide in Mitochondria.” The full list of papers may be found on the homepage of the journal.