Reversal of both peroxisomal and mitochondrial dysfunction with natural products

用天然产物逆转过氧化物酶体和线粒体功能障碍

基本信息

批准号：
489096-2015
负责人：
Weaver, Ian
金额：
$ 1.81万
依托单位：
Dalhousie University
依托单位国家：
加拿大
项目类别：
Engage Grants Program
财政年份：
2015
资助国家：
加拿大
起止时间：
2015-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=586448
关键词：
Reversal both peroxisomal mitochondrial dysfunction

项目摘要

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.

线粒体功能障碍导致有害活性氧的过量产生被认为是细胞衰老的核心机制。然而，线粒体抗氧化剂不能延长动物的寿命表明其他机制也导致衰老。缩醛磷脂是细胞膜的重要成分，占线粒体总脂质的很大一部分内容。这些醚脂完全由过氧化物酶体产生，过氧化物酶体是已知会随着年龄的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并促进细胞死亡的功能障碍。这些造成的线粒体缺陷增加新过氧化物酶体和线粒体产生的化合物可以减弱突变。这些发现表明过氧化物酶体和线粒体在功能上是相互关联的，并表明这两种细胞器都应以减少氧化应激和促进细胞存活为目标。为了检验这个假设，我将确定已知的膳食类黄酮（表儿茶素和槲皮素）是否具有保护作用改善线粒体功能，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。这将完成通过确定口服表儿茶素、槲皮素和缩醛磷脂前体是否会减少使用已知的化疗药物顺铂治疗的小鼠会出现听力损失和肾脏损伤破坏过氧化物酶体和线粒体的功能。