Persistent mitochondrial damage by nitric oxide and its derivatives: neuropathological implications
Open Access
- 1 January 2010
- journal article
- Published by Frontiers Media SA in Frontiers in Neuroenergetics
Abstract
Approximately 15 years ago we reported that cytochrome c oxidase (CcO) was persistently inhibited as a consequence of endogenous induction and activation of nitric oxide (•NO) synthase-2 (NOS2) in astrocytes. Furthermore, the reactive nitrogen species implicated was peroxynitrite. In contrast to the reversible inhibition by •NO, which occurs rapidly, in competition with O2, and has signaling regulatory implications, the irreversible CcO damage by peroxynitrite is progressive in nature and follows and/or is accompanied by damage to other key mitochondrial bioenergetic targets. In purified CcO it has been reported that the irreversible inhibition occurs through a mechanism involving damage of the heme a3-CuB binuclear center leading to an increase in the Km for oxygen. Astrocyte survival, as a consequence of peroxynitrite exposure, is preserved due to their robust bioenergetic and antioxidant defense mechanisms. However, by releasing peroxynitrite to the neighboring neurons, whose antioxidant defense can, under certain conditions, be fragile, activated astrocytes trigger bioenergetic stress leading to neuronal cell death. Thus, such irreversible inhibition of CcO by peroxynitrite may be a plausible mechanism for the neuronal death associated with neurodegenerative diseases, in which the activation of astrocytes plays a crucial role.Keywords
This publication has 80 references indexed in Scilit:
- PKA-Dependent Phosphorylation of Serum Response Factor Inhibits Smooth Muscle–Specific Gene ExpressionArteriosclerosis, Thrombosis, and Vascular Biology, 2009
- Reduced glutathione is highly expressed in white matter and neurons in the unperturbed mouse brain — Implications for oxidative stress associated with neurodegenerationBrain Research, 2009
- Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disordersJournal of Neurochemistry, 2009
- Nrf2 Activation in Astrocytes Protects against Neurodegeneration in Mouse Models of Familial Amyotrophic Lateral SclerosisJournal of Neuroscience, 2008
- Concepts of neural nitric oxide‐mediated transmissionEuropean Journal of Neuroscience, 2008
- Astrocytes in multiple sclerosis: A product of their environmentCellular and Molecular Life Sciences, 2008
- The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?Trends in Neurosciences, 2008
- Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: A possible explanation for hypoxic vasodilationProceedings of the National Academy of Sciences of the United States of America, 2007
- Cellular pathways of energy metabolism in the brain: Is glucose used by neurons or astrocytes?Glia, 2007
- Nitric Oxide and Peroxynitrite in Health and DiseasePhysiological Reviews, 2007