Project: Research project

Project Details


DESCRIPTION Mitochondria are known to be the primary
source of oxidative stress in most cells. Oxidative stress is also known to be
one of the most potent inducers of apoptosis, and mitochondria have been shown
to play a critical role in the regulation of oxidant-stress induced apoptosis
through the release of apoptogenic factors that activate a specific class of
cysteine proteases (caspases), leading to cell death. Low-level oxidant stress
over the lifespan of an organism has been hypothesized to lead to the
accumulation of damaged mitochondria resulting in the age-dependent
declination in overall physiological function. The juxtaposition of
mitochondria as the chief site of production and major target of oxidative
stress, their pivotal role in apoptosis, and the fact that oxidative damage to
mitochondrial proteins, lipids and DNA as well as the proportion of damaged
mitochondria increases with age, suggests that age-dependent oxidative-induced
alterations in mitochondrial function and their attendant effects on
apoptosis, may contribute to the aging process. In this proposal, we wish to
test the hypothesis that oxidative stress over the lifespan of an organism,
leads to failure of normal apoptotic regulation, resulting in altered
apoptosis which contributes to aging. The specific alms of this project will
be to determine: a) if the temporal onset and the mechanisms regulating
oxidant stress-induced mitochondrial apoptosis differ as a function of the age
and/or antioxidant defenses of the cell; and b) whether oxidant stress induced
alterations in the activity of other (non-mitochondrial) components of the
apoptotic pathway differ as a function of the age and/or antioxidant defenses
of the cell. These studies will employ examination of oxidant stress-induced
apoptotic pathways in hepatocytes from mice and rats of different ages under
conditions where the level of mitochondrial antioxidant defenses has been
genetically manipulated in conjunction with technologies to directly assess
mitochondrial function and apoptosis insitu. Results from these studies will
provide information about whether oxidant-induced-age-dependent differences in
the regulation of mitochondrial and non-mitochondrial apoptosis exist and if
modulation of the level of steady state oxidative damage in the mitochondria
as a function of age impacts age-dependent mitochondrial function and
Effective start/end date4/1/011/31/13


  • National Institutes of Health


  • Medicine(all)


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