Nitric oxide, mitochondria and neurological disease

Abstract

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state. Within the brain, the susceptibility of different brain cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage. Thus neurones, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules. Following cytokine exposure, astrocytes can increase NO generation, due to de novo synthesis of the inducible form of nitric oxide synthase (NOS). Whilst the NO/ONOO- so formed may not affect astrocyte survival, these molecules may diffuse out to cause mitochondrial damage, and possibly cell death, to other cells, such as neurones, in close proximity. Evidence is now available to support this scenario for neurological disorders, such as multiple sclerosis. In other conditions, such as ischaemia, increased availability of glutamate may lead to an activation of a calcium-dependent nitric oxide synthase associated with neurones. Such increased/inappropriate NO formation may contribute to energy depletion and neuronal cell death. The evidence available for NO/ONOO--mediated mitochondrial damage in various neurological disorders is considered and potential therapeutic strategies are proposed.

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Lipases are also activated by calcium, further increasing the production of free radical species (Farooqui and Horrocks, 1994). The neuronal isoform of nitric oxide synthase (NOS) is also activated by Ca 2+ and ischemia-associated NO overproduction perturbs ATP synthesis and induces the release of proteins involved in cell death (Heales et al, 1999).…”

Hydrogen peroxide generated at the level of mitochondria in response to peroxynitrite promotes U937 cell death via inhibition of the cytoprotective signalling mediated by cytosolic phospholipase A2

“…Although NO regulates various cell functions, [1][2][3][4] its excessive or inappropriate formation might cause deleterious effects relevant in various human pathologies. [3][4][5] A large proportion of these toxic effects appears to be mediated by peroxynitrite, the coupling product of NO and superoxide. [5][6][7] The wellestablished notion that peroxynitrite is a highly reactive nitrogen species has long been considered as a straightforward indication that the deleterious effects mediated by this species are entirely ascribable to its direct interactions with target biomolecules.…”

“…[3][4][5] A large proportion of these toxic effects appears to be mediated by peroxynitrite, the coupling product of NO and superoxide. [5][6][7] The wellestablished notion that peroxynitrite is a highly reactive nitrogen species has long been considered as a straightforward indication that the deleterious effects mediated by this species are entirely ascribable to its direct interactions with target biomolecules. These effects include lipid peroxidation, 8 protein nitration and nitrosylation, 9 DNA damage 10 and oxidation of thiols, 11 and are thought to result in mitochondrial dysfunction and cytotoxicity.…”

Cell signaling and cytotoxicity by peroxynitrite.

“…NO regulates various cell functions via cyclic GMP-dependent and -independent mechanisms (3,4), and these effects are critical in the physiological regulation of nervous, immune, and vascular systems. It is important to note, however, that excessive or inappropriate formation of NO might cause deleterious effects relevant in various human pathologies such as acute endotoxemia, neurological disorders, atherosclerosis, and ischemia/reperfusion (3,5). Although NO can be directly detrimental to target cells, most of its toxic effects appear to be mediated by peroxynitrite, the coupling product of NO and superoxides (5)(6)(7).…”