Reversal of both peroxisomal and mitochondrial dysfunction with natural products

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Mitochondrial dysfunction resulting in the excessive production of injurious reactive oxygen species is considered to be a central mechanism in cellular senescence. However, mitochondrial anti-oxidants fail to improve the longevity of animals suggesting that other mechanisms contribute to aging. Plasmalogens are essential components of cell membranes that comprise a large proportion of the total mitochondrial lipid content. These ether lipids are produced exclusively by peroxisomes, organelles known to decline with age resulting in reduced plasmalogen synthesis. Mutations that impair plasmalogen synthesis lead to mitochondrial dysfunction that causes oxidative stress and promotes cell death. Mitochondrial deficits produced by these mutations are attenuated by compounds that increase the production of new peroxisomes and mitochondria. These findings indicate that peroxisomes and mitochondria are functionally inter-connected and suggest that both organelles should be targeted to reduce oxidative stress and promote cell survival. To test this hypothesis, I will determine whether the protective effects of dietary flavonoids (epicatechin and quercetin), known to improve mitochondrial function, are enhanced by the administration of plasmalogen precursors in a mouse model of oxidative injury characterized by both peroxisomal and mitochondria dysfunction. This will be done by determining whether oral administration of epicatechin, quercetin and plasmalogen precursors reduce hearing loss and kidney damage in mice treated with the chemotherapeutic drug cisplatin that is known to disrupt the function of peroxisomes and mitochondria.