Mitochondria as metabolizers and targets of nitrite

Abstract

Mitochondrial function is integral to maintaining cellular homeostasis through the production of ATP, the generation of reactive oxygen species (ROS) for signaling, and the regulation of the apoptotic cascade. A number of small molecules, including nitric oxide (NO), are well-characterized regulators of mitochondrial function. Nitrite, an NO metabolite, has recently been described as an endocrine reserve of NO that is reduced to bioavailable NO during hypoxia to mediate physiological responses. Accumulating data suggests that mitochondria may play a role in metabolizing nitrite and that nitrite is a regulator of mitochondrial function. Here, what is known about the interactions of nitrite with the mitochondria is reviewed, with a focus on the role of the mitochondrion as a metabolizer and target of nitrite.

(c) 2009 Elsevier Inc. All rights reserved.

Figures

Figure 1. Sites of mitochondrial nitrite reduction

(A) In normoxia, electrons enter the respiratory chain at complex I or II and are shuttled through the Q cycle to complex III. While most electrons are then shuttled to cytochrome c and then to complex IV, where oxygen binds the binuclear center (cyta3 CuB) and acts as the terminal electron acceptor, some electrons escape at complex III to generate superoxide. Protons are pumped from the matrix to the intermembrane space through the complexes to set up a proton gradient for ATP generation. (B) During hypoxia, nitrite can be reduced at complex III or cytochrome c oxidase (complex IV). If cytochrome c is converted to its pentacoordinate form (through oxidation, nitration or association with anionic lipid), it can act as a site of nitrite reduction.

Figure 2. Nitrite-dependent extension of oxygen gradients

(A) During normoxia, NOS is functional, myoglobin is oxygenated, and sufficient oxygen is available to diffuse from the source of oxygen through the tissue. (B) In hypoxic conditions, NOS is substrate limited and cannot make NO and myoglobin becomes deoxygenated. The majority of oxygen present is consumed by mitochondria close to the oxygen source, leading to a shortened oxygen gradient. (C) If nitrite is present during hypoxic conditions, it can be reduced by deoxygenated myoglobin. The NO generated can then partially inhibit mitochondrial oxygen consumption, allowing more oxygen to diffuse past these mitochondria and further into the tissue (elongation of oxygen gradient).

Figure 3. S-nitrosation of mitochondria and decreased ROS generation after anoxia/reoxygenation

Isolated rat liver mitochondria treated with nitrite (2.5–100µM) during anoxia show a (A) concentration dependent increase in S-nitrosation and (B) a concomitant inhibition of complex I activity. (C) Nitrite treatment (10 µM) during anoxia prevents hydrogen peroxide generation at reoxygenation.

Figure 4. Nitrite regulates mitochondrial function

During hypoxia, nitrite is reduced to NO by deoxygenated myoglobin and nitrosylates the binuclear center of complex IV. This results in the inhibition of oxygen consumption which may contribute to the regulation of oxygen gradients and the modulation of exercise efficiency. During ischemia/reperfusion, nitrite is converted to a nitrosating species (possibly N2O3 through its reductive anhydrase reaction with heme) and S-nitrosates complex I at reperfusion. This leads to decreased ROS generation and inhibition of cytochrome c release, which contribute to cytoprotection after I/R.