Reversal of both peroxisomal and mitochondrial dysfunction with natural products

线粒体功能障碍导致有害活性氧的过度产生， 被认为是细胞衰老的中心机制。然而，线粒体抗氧化剂不能 延长动物的寿命，这表明其他机制有助于衰老。缩醛磷脂是 细胞膜的基本成分，占线粒体总脂质的很大比例 内容这些醚脂完全由过氧化物酶体产生，过氧化物酶体是一种已知会随年龄增长而衰退的细胞器 导致缩醛磷脂合成减少。损害缩醛磷脂合成的突变导致线粒体 导致氧化应激和促进细胞死亡的功能障碍。线粒体缺陷产生的这些 突变被增加新过氧化物酶体和线粒体产生的化合物减弱。 这些发现表明，过氧化物酶体和线粒体在功能上是相互连接的，并表明， 两种细胞器都应该被靶向以减少氧化应激并促进细胞存活。为了验证这个假设， 我将确定膳食类黄酮（表儿茶素和槲皮素）的保护作用，已知， 改善线粒体功能，通过在小鼠中施用缩醛磷脂前体来增强 以过氧化物酶体和线粒体功能障碍为特征的氧化损伤模型。为此将 通过测定口服施用表儿茶素、槲皮素和缩醛磷脂前体是否减少 在用化疗药物顺铂治疗的小鼠中， 破坏过氧化物酶体和线粒体的功能。

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.