Oxidative Stress and Mitochondrial DNA Mutations in Human Aging
Oxidative Stress and Mitochondrial DNA Mutations in Human Aging
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DOI：
10.3181/00379727-217-44205
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发表时间：
1998-01
影响因子：
--
通讯作者：
Yau-Huei Wei
中科院分区：
文献类型：
--
作者：
Yau-Huei Wei
摘要 线粒体呼吸系统是细胞内活性氧（ROS）和自由基的主要来源，这些活性氧和自由基是在正常生理条件下电子从 NADH 或 FADH2 转移到分子氧过程中产生的副产物。这些可能逃脱人类和动物细胞防御机制的有毒副产物的比例随着年龄的增长而增加，可能会对线粒体和整个细胞中的生物分子产生广泛的氧化损伤。大量证据表明，衰老过程中组织细胞线粒体中的氧化应激和相关氧化损伤逐渐升高。线粒体 DNA (mtDNA) 虽然不受组蛋白或 DNA 结合蛋白的保护，但会持续暴露于线粒体基质中高稳态水平的 ROS 和自由基中。因此，线粒体DNA的氧化修饰和突变非常容易发生，并且线粒体DNA的这种改变的程度随着年龄的增长而呈指数增长。 ROS含量不断增加，导致线粒体内脂质过氧化和蛋白质氧化修饰同时增强，进一步加剧了衰老过程中线粒体DNA的突变和氧化损伤。含有缺陷mtDNA编码蛋白亚基的呼吸酶表现出电子传递功能受损，从而增加电子泄漏和ROS产生，进而加剧线粒体的氧化应激和氧化损伤。这种恶性循环以不同的速率在各种组织细胞中运作，并导致氧化修饰和突变 mtDNA 的差异积累。这或许可以解释人类衰老过程中不同器官和组织的功能衰退和结构退化的差异。线粒体和 mtDNA 的改变在衰老和与年龄相关的退行性疾病中可能发挥的核心作用将与“线粒体衰老理论”相关讨论。
Abstract The mitochondrial respiratory system is the major intracellular source of the reactive oxygen species (ROS) and free radicals, which are generated as byproducts during the transfer of electrons from NADH or FADH2 to molecular oxygen under normal physiological conditions. An age-dependent increase in the fraction of these toxic byproducts that may escape the defense mechanism of human and animal cells can induce a broad spectrum of oxidative damage to the biomolecules in the mitochondria and the cell as a whole. Abundant evidence has been gathered to suggest that an elevation of oxidative stress and associated oxidative damages gradually occur in the mitochondria of tissue cells during aging. The mitochondrial DNA (mtDNA), while not protected by histones or DNA-binding proteins, is continually exposed to a high steady-state level of ROS and free radicals in the matrix of the mitochondria. Thus, oxidative modification and mutation of mtDNA occur with great ease, and the extent of such alterations of mtDNA increases exponentially with age. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria elicited by the ever-increasing amount of the ROS further aggravate the mutation and oxidative damage to mtDNA in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits exhibit impaired electron transport function and thereby increase the electron leak and ROS production, which in turn elevate the oxidative stress and oxidative damage to mitochondria. This vicious cycle operates in various tissue cells at different rate and leads to differential accumulation of oxidatively modified and mutant mtDNAs. This may explain the difference in functional decline and structural deterioration of different organs and tissues in human aging. The central role that alterations of the mitochondria and mtDNA may play in aging and age-related degenerative diseases is discussed in relation to the “Mitochondrial theory of aging.”