Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases.
Within the CNS and under normal conditions, nitric oxide (.NO) appears to be an important physiological signalling molecule. Its ability to increase cyclic GMP concentration suggests that .NO is implicated in the regulation of important metabolic pathways in the brain. Under certain circumstances .NO synthesis may be excessive and .NO may become neurotoxic. Excessive glutamate-receptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both .NO and superoxide (O2.-) and hence peroxynitrite (ONOO-) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of .NO, which may be deleterious to the neighbouring neurones and oligodendrocytes. The precise mechanism of .NO neurotoxicity is not fully understood. One possibility is that it may involve neuronal energy deficiency. This may occur by ONOO- interfering with key enzymes of the tricarboxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation of the energy-consuming pathway involving poly(ADP-ribose) synthetase. Possible mechanisms whereby ONOO- impairs the mitochondrial respiratory chain and the relevance for neurotoxicity are discussed. The intracellular content of reduced glutathione also appears important in determining the sensitivity of cells to ONOO- production. It is concluded that neurotoxicity elicited by excessive .NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.
Bolaños
J P
JP
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Salamanca, Spain.
Almeida
A
A
Stewart
V
V
Peuchen
S
S
Land
J M
JM
Clark
J B
JB
Heales
S J
SJ
D000818:Animals; D001927:Brain Diseases / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009410:Nerve Degeneration / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*
D009569:Nitric Oxide