Mitochondrial Dysfunction

Perhaps one of the most important consequences of NO production in MS lesions will prove to be an inhibition of mitochondrial respiration, leading to a reduced, and perhaps insufficient, production of ATP. At present it is not certain that NO has these effects in MS lesions, but there is a weight of circumstantial evidence suggesting this may be so.

The effects of NO on mitochondria have been the subject of several recent reviews (Brown and Bal-Price, 2003; Brown and Borutaite, 2002; Duchen, 2000, 2004; Brorson et al., 1999; Beltran et al., 2000a). In brief, there is good evidence that NO and its related molecules are potent in inhibiting enzymes of the respiratory chain. In particular, NO exerts an acute, potent, and reversible inhibition of cytochrome c oxidase (complex IV, the terminal component of the mitochon-drial respiratory chain) in competition with oxygen (Brown and Cooper, 1994; Cleeter et al., 1994; Sarti et al., 2003), and reactive nitrogen species, such as peroxynitrite, can also irreversibly inhibit the respiratory pathway at several additional stages, including complexes I, II, and V (reviewed in Brown and Borutaite, 2002; Radi et al., 2002). The inhibition of these key components of mitochondrial respiration understandably reduces ATP production (Brookes et al., 1999; Brorson et al., 1999), and this can be expected to have prompt and marked deleterious consequences in axons because they have high energy demands. For example, a reduction in ATP could easily be sufficient to result in a failure to maintain the axonal ion gradients upon which conduction and normal axonal physiology depend (Ames III, 2000). Some potential consequences of this failure are discussed in the section NO and Axonal Degeneration.

There is an ongoing debate regarding whether NO may affect mitochondrial metabolism at physiological concentrations (e.g., Brown et al., 1995; Brown, 2000; Bellamy et al., 2002; Moncada and Erusalimsky, 2002; Keynes and Garthwaite, 2004; Brookes et al., 2003); that is, whether NO exists at a sufficient concentration in the normal nervous system to achieve a significant inhibition of cytochrome c oxidase. However, NO-mediated mitochondrial inhibition is less controversial when pathological concentrations of NO are concerned. Thus at tissue oxygen concentrations (e.g., 5-30,uM oxygen), NO at only 100 nM concentration achieves an approximately 60% inhibition of mitochondrial respiration, at least in vitro, with a K reported to be as low as 27 or 60 nM (Fig. 3) (Brown, 2000; Brown and Cooper, 1994; Koivisto et al., 1997; Brookes et al., 2003). Although the NO concentration within MS lesions is not known, it seems likely that it will reach or exceed these levels, especially in the more intensely inflammatory lesions where iNOS-positive cells are plentiful. Furthermore, the effects of NO are significantly augmented by hypoxia, and there is recent evidence that hypoxia-like conditions exist within some MS lesions (Aboul-Enein et al., 2003). Moreover, the likelihood of irreversible damage to mitochondrial function increases not only with exposure to higher NO concentrations, but also with prolonged exposure to NO (Brookes et al., 1999; Beltran et al., 2000b; Stewart et al., 2000; Clementi et al., 1998), and such exposure will certainly occur in inflammatory MS lesions. On the basis of magnetic resonance imaging (MRI) observations, inflammation can persist within lesions for weeks or months.

NO can also open the mitochondrial permeability transition pore (Horn et al., 2002), a large conductance pore that, when open, can cause a collapse of the mitochondrial membrane potential, leading to ATP depletion (reviewed in Duchen, 2004). There is also evidence that the overall reduction in ATP synthesis can be sufficiently profound in neurons so that NO probably also inhibits glycolysis (Brorson et al., 1999), such as by the inhibition of glyceraldehyde-3-phosphate dehydrogenase (Brune and Mohr, 2001).

Apart from compromising ATP production, inhibition of complex IV can result in the increased production of super-

100 200 300 400 [Nitric oxidel] nM

Figure 3 Curves showing the effect of different concentrations of NO on mitochondrial metabolism at two concentrations of oxygen. The potency of NO is enhanced at tissue concentrations of oxygen (~30mM). (Reproduced from Brown, 2000.)

100 200 300 400 [Nitric oxidel] nM

Figure 3 Curves showing the effect of different concentrations of NO on mitochondrial metabolism at two concentrations of oxygen. The potency of NO is enhanced at tissue concentrations of oxygen (~30mM). (Reproduced from Brown, 2000.)

oxide and other reactive oxygen species by mitochondria, with the likely consequence of an increased damaging production of peroxynitrite (Moncada and Erusalimsky, 2002; Brown and Borutaite, 2001). Beyond inhibiting several key molecules within mitochondria, this strong oxidizing agent will have additional deleterious effects on proteins, lipids, and other targets within MS lesions.

Several lines of evidence suggest that mitochondrial function is indeed impaired in MS and EAE, in line with expectations based on the previous observations, although whether NO is responsible for the impairment is not yet clear. However, oxidative damage to mitochondrial DNA has been reported in active MS plaques (Vladimirova et al., 1998; Lu et al., 2000) associated with an impaired NADH dehydrogenase activity (Lu et al., 2000). A pronounced reduction in the axonal density of ATPase-positive mitochondria has been described in a subset of acutely demyelinating plaques (reported in Smith and Lassmann, 2002). Microarray analysis of MS normal-appearing white matter has also revealed the upregulation of genes that reflect a higher energy metabolism (Graumann et al., 2003). The cause for this upregulation is not yet clear, but it is arguably in compensation for a diminished energy production from the existing mitochondria. The same study reported evidence suggesting a global defense against oxidative and perhaps nitrosative stress. In EAE, an inhibition of respiratory chain function has been reported in brain macrophage/microglial cells (Zielasek et al., 1995), and a lactic acidosis has also been noted during the onset of clinical signs (Simmons et al., 1982).

Demyelinated regions of axons might be especially vulnerable to an inhibition of mitochondrial respiration on the basis of the observation that they possess greater numbers of mitochondria than normal (Mutsaers and Carroll, 1998). This finding suggests that energy demand is higher in demyelinated than in normal axons, and it is easy to imagine many reasons why this should be so. For example, although unproven, it seems certain that the sodium load incurred per conducted action potential will be much greater along demyelinated membranes in comparison with the normally myelinated portions of the same axon (see Chapter 6).

Finally, it has recently been reported that NO can trigger the biogenesis of mitochondria in some cell types, by a cGMP-dependent mechanism (Nisoli et al., 2003). Whether such an event occurs within the CNS in MS has not been examined, but, if it occurs, it could tend to diminish the deleterious consequences of some of the phenomena described previously.

Your Metabolism - What You Need To Know

Your Metabolism - What You Need To Know

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