Mitochondrial Oxidative Stress and Therapeutics
S.L. Melov
Buck Institute for Age Research,
8001 Redwood Blvd.,
Novato, CA 94945 USA
The free radical theory of aging now has substantial experimental
support as explaining some of the degenerative processes of aging. Free
radicals are produced as a byproduct of energy metabolism in the
mitochondria. In order to better understand the consequences of
endogenous free radical production, we have been characterizing mice
which lack superoxide dismutase located in the matrix of the
mitochondria (SOD2-/- mice). These mice have a neonatal lethal
phenotype accompanied by hepatic lipid accumulation, neuronal cell
death, cardiac dysfunction, mitochondrial biochemical abnormalities,
and oxidative damage. Treatment of SOD2-/- mice with synthetic
catalytic antioxidants, rescues or attenuates many of the phenotypes
associated with endogenous oxidative stress. These catalytic
antioxidants, which are both SOD and catalase mimetics, are also able
to extend the natural lifespan of the nematode caenorhabditis elegans.
This demonstrates the efficacy of these compounds in attenuating
oxidative stress in either acute (mammals) or chronic (C.elegans)
physiological situations. In order to further our understanding of
mitochondrial oxidative stress, we have been characterizing the
pharmacogenomic and proteomic profiles associated with oxidative
stress.
Key words:
mitochondria, oxidative stress, antioxidant, mouse
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