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Persistent mitochondrial damage by nitric oxide and its derivatives: neuropathological implications.

BolaƱos JP, Heales SJ - Front Neuroenergetics (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Institute of Neurosciences of Castilla- Leon, University of Salamanca Salamanca, Spain.

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 O(2), 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 a(3)-Cu(B) binuclear center leading to an increase in the K(m) 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.

No MeSH data available.


Related in: MedlinePlus

Role for irreversible inhibition of cytochrome c oxidase in neurodegeneration. Peroxynitrite can be formed in astrocytes upon activation. In astrocytes, peroxyntrite irreversibly damages cytochrome c oxidase, which causes mitochondrial dysfunction. However, these cells compensate the energy deficiency by activating glycolysis and survive. Peroxynitrite is a highly diffusible molecule, and hence it reaches neighboring neurons, where it irreversibly damages cytochrome c oxidase. In contrast to astrocytes, neurons cannot up-regulate the energy-compensating glycolysis and hence they die by bioenergetic crisis. Thus, the irreversible inhibition of cytochrome c oxidase by peroxynitrite has a critical negative effect on neuronal survival and may contribute to the propagation of neurodegeneration.
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Figure 1: Role for irreversible inhibition of cytochrome c oxidase in neurodegeneration. Peroxynitrite can be formed in astrocytes upon activation. In astrocytes, peroxyntrite irreversibly damages cytochrome c oxidase, which causes mitochondrial dysfunction. However, these cells compensate the energy deficiency by activating glycolysis and survive. Peroxynitrite is a highly diffusible molecule, and hence it reaches neighboring neurons, where it irreversibly damages cytochrome c oxidase. In contrast to astrocytes, neurons cannot up-regulate the energy-compensating glycolysis and hence they die by bioenergetic crisis. Thus, the irreversible inhibition of cytochrome c oxidase by peroxynitrite has a critical negative effect on neuronal survival and may contribute to the propagation of neurodegeneration.

Mentions: Due to its high-energy requirements to support ionic balance and neurotranmission (Hertz et al., 2007; Nehlig and Coles, 2007; Pellerin et al., 2007; Cai and Sheng, 2009), the central nervous system is one of the most vulnerable targets to mitochondrial impairment. However, the brain is a complex tissue formed by the organization of four well-differentiated neural cell types, including neurons, astrocytes, microglia and oligodendrocytes (Hertz et al., 2007). Such cell types do not act in isolation, as a degree of active collaboration exists between the differing cells, e.g. astrocytes are involved in glutamate homeostasis and the trafficking of antioxidants to neuronal cells (Fellin, 2009; Perea et al., 2009). Furthermore, astrocytes and neurons establish a mutual paracrine-like communication system through the release of soluble and cell permeable factors, involving cytokines (Peuchen et al., 1997), reactive oxygen and nitrogen species (RONS) (Whitney et al., 2009) or substrate precursors (Pellerin et al., 2007) (Figure 1).


Persistent mitochondrial damage by nitric oxide and its derivatives: neuropathological implications.

BolaƱos JP, Heales SJ - Front Neuroenergetics (2010)

Role for irreversible inhibition of cytochrome c oxidase in neurodegeneration. Peroxynitrite can be formed in astrocytes upon activation. In astrocytes, peroxyntrite irreversibly damages cytochrome c oxidase, which causes mitochondrial dysfunction. However, these cells compensate the energy deficiency by activating glycolysis and survive. Peroxynitrite is a highly diffusible molecule, and hence it reaches neighboring neurons, where it irreversibly damages cytochrome c oxidase. In contrast to astrocytes, neurons cannot up-regulate the energy-compensating glycolysis and hence they die by bioenergetic crisis. Thus, the irreversible inhibition of cytochrome c oxidase by peroxynitrite has a critical negative effect on neuronal survival and may contribute to the propagation of neurodegeneration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822548&req=5

Figure 1: Role for irreversible inhibition of cytochrome c oxidase in neurodegeneration. Peroxynitrite can be formed in astrocytes upon activation. In astrocytes, peroxyntrite irreversibly damages cytochrome c oxidase, which causes mitochondrial dysfunction. However, these cells compensate the energy deficiency by activating glycolysis and survive. Peroxynitrite is a highly diffusible molecule, and hence it reaches neighboring neurons, where it irreversibly damages cytochrome c oxidase. In contrast to astrocytes, neurons cannot up-regulate the energy-compensating glycolysis and hence they die by bioenergetic crisis. Thus, the irreversible inhibition of cytochrome c oxidase by peroxynitrite has a critical negative effect on neuronal survival and may contribute to the propagation of neurodegeneration.
Mentions: Due to its high-energy requirements to support ionic balance and neurotranmission (Hertz et al., 2007; Nehlig and Coles, 2007; Pellerin et al., 2007; Cai and Sheng, 2009), the central nervous system is one of the most vulnerable targets to mitochondrial impairment. However, the brain is a complex tissue formed by the organization of four well-differentiated neural cell types, including neurons, astrocytes, microglia and oligodendrocytes (Hertz et al., 2007). Such cell types do not act in isolation, as a degree of active collaboration exists between the differing cells, e.g. astrocytes are involved in glutamate homeostasis and the trafficking of antioxidants to neuronal cells (Fellin, 2009; Perea et al., 2009). Furthermore, astrocytes and neurons establish a mutual paracrine-like communication system through the release of soluble and cell permeable factors, involving cytokines (Peuchen et al., 1997), reactive oxygen and nitrogen species (RONS) (Whitney et al., 2009) or substrate precursors (Pellerin et al., 2007) (Figure 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Institute of Neurosciences of Castilla- Leon, University of Salamanca Salamanca, Spain.

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 O(2), 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 a(3)-Cu(B) binuclear center leading to an increase in the K(m) 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.

No MeSH data available.


Related in: MedlinePlus