Reversal of both peroxisomal and mitochondrial dysfunction with natural products

线粒体功能障碍导致伤害性活性氧的过量产生 被认为是细胞衰老的中心机制。然而，线粒体抗氧化剂不能 提高动物的寿命，这表明其他机制也有助于衰老。血浆原是 细胞膜的基本成分，占线粒体总脂质的很大比例 内容。这些乙醚类脂完全由过氧化物体产生，这些细胞器会随着年龄的增长而衰退。 导致血浆蛋白原合成减少。破坏血浆蛋白原合成的突变导致线粒体 导致氧化应激并促进细胞死亡的功能障碍。由这些产生的线粒体缺陷 通过增加新的过氧化物体和线粒体的产生的化合物来减弱突变。 这些发现表明，过氧化物体和线粒体在功能上是相互联系的，并表明 这两个细胞器都应该以减少氧化应激和促进细胞生存为目标。为了检验这一假设， 我将确定饮食中的类黄酮(表儿茶素和槲皮素)是否具有保护作用，已知 改善线粒体功能，通过给小鼠注射纤溶酶原前体而增强 以过氧化体和线粒体功能障碍为特征的氧化损伤模型。这件事会做到的 通过确定口服表儿茶素、栎素和纤溶酶原前体是否会减少 化疗药物顺铂治疗小鼠的听力损失和肾脏损害 破坏过氧化物体和线粒体的功能。

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.