Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration.
Excessive generation of nitric oxide (NO) has been implicated in the pathogenesis of several neurodegenerative disorders. Damage to the mitochondrial electron transport chain has also been implicated in these disorders. NO and its toxic metabolite peroxynitrite (ONOO(-)) can inhibit the mitochondrial respiratory chain, leading to energy failure and ultimately cell death. There appears to be a differential susceptibility of brain cell types to NO/ONOO(-), which may be influenced by factors including cellular antioxidant status and the ability to maintain energy requirements in the face of marked respiratory chain damage. Although formation of NO/ONOO(-) following cytokine exposure does not affect astrocyte survival, these molecules may diffuse out and cause mitochondrial damage to neighboring NO/ONOO(-)-sensitive cells such as neurons. Evidence suggests that NO/ONOO(-) causes release of neuronal glutamate, leading to glutamate-induced activation of neuronal NO synthase and generation of further damaging species. While neurons appear able to recover from short-term exposure to NO/ONOO(-), extending the period of exposure results in persistent damage to the respiratory chain and cell death ensues. These findings have important implications for acute infection vs. chronic neuroinflammatory disease states. The evidence for NO/ONOO(-)-mediated mitochondrial damage in neurodegenerative disorders is reviewed and potential therapeutic strategies are discussed.
Stewart
Victoria C
VC
Department of Molecular Pathogenesis, Division of Neurochemistry, Institute of Neurology, University College London, London, England.
Heales
Simon J R
SJ
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D019966:Substance-Related Disorders
D009569:Nitric Oxide