UBIQUINONE AND MITOCHONDRIAL OXIDATIVE DISORDERS OF AGIN

描述：(逐字摘自申请者的摘要)长期目标 该提案的目的是阐明线粒体相关的细胞凋亡的机制。 与衰老和神经退行性疾病有关。人线粒体 DNA(MtDNA)缺失突变在一些神经退行性疾病中被发现 疾病，包括Kearns-Sayre综合征，Leber遗传性视神经病变， 阿尔茨海默氏症、帕金森氏症，以及随着年龄的增长。中的异常现象 线粒体代谢同样与神经退行性变有关。 疾病，如亨廷顿病。此外，有氧能量的下降 受影响组织中的新陈代谢通常与 这些神经退行性疾病。有氧代谢的下降一直是 在老化的组织中观察到。泛醌(辅酶Q10)除了它的 线粒体电子传递中的电子和质子载体作用 与ATP合成相结合，以其还原形式(泛硫醇)作为 抗氧化剂，抑制生物膜中的脂质过氧化和 保护线粒体内膜蛋白和DNA免受氧化损伤 损害伴随的脂质过氧化。泛喹酚是唯一已知的 动物细胞可以从头合成和形成的脂溶抗氧化剂 其中存在酶机制，可以从其氧化后再生 产物在其抗氧化作用过程中形成。组织泛黄酮类 水平受与下列因素相关的生理因素的调节 生物体的氧化活性：它们在 氧化应激，如体育锻炼、冷适应、甲状腺激素 治疗，并在老化过程中减少。这项建议的具体目标是： A)确定药物的自然分布和综合药代动力学 辅酶Q10中辅酶Q10的参数及其区域分布 CNS；B)通过以下方式寻找与神经退行性变有关的分子链接之一 研究泛素、ATP依赖通路、G肌动蛋白和 神经元中的神经丝；c)测试神经保护剂如 司来吉兰对纹状体、海马区和皮质辅酶Q10水平的影响； D)探讨抗氧化剂协同调节对Mn++状态的影响 线粒体中发现的超氧化物歧化酶、铜、锌+超氧化物歧化酶 位于细胞质中；辅酶Q10在线粒体和 细胞质；以及E)了解辅酶Q10的使用 可以保护神经胶质细胞和神经元免受MPTP等神经毒素的伤害 导致帕金森病或NMDA-和非NMDA受体激活导致 兴奋性毒物对钙离子稳态的破坏和随后的氧化应激。这个 这些研究的完成无疑将提供更多的项目 活性氧引起线粒体DNA损伤的研究进展 辅酶Q10(泛喹酚)的保护作用将其降至最低。

DESCRIPTION: (Verbatim from the Applicant's Abstract) The long-term objective of the proposal is to clarify the mechanism of mitochondrial-linked apoptosis associated with aging and neurodegenerative disorders. Human mitochondrial DNA(mtDNA) deletion mutations have been found in a number of neurodegenerative diseases, including Kearns-Sayre syndrome, Leber's hereditary optic neuropathy, Alzheimer's disease, and Parkinson's disease, and with aging. Abnormalities in mitochondrial metabolism likewise have been associated with neurodegenerative disease, e.g., Huntington's disease. In addition, a decline of aerobic energy metabolism in the affected tissue is often associated with the progression of these neurodegenerative diseases. A decline in aerobic metabolism has been observed in aging tissues. Ubiquinone(coenzyme Q10), in addition to its function as an electron and proton carrier in mitochondrial electron transport coupled to ATP synthesis, acts in its reduced form(ubiqionol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and protecting mitochondrial inner-membrane proteins and DNA against oxidative damage accompanying lipid peroxidation. Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo and for which there exists enzymic mechanisms which can regenerate it from its oxidized product formed in the course of its antioxidant function. Tissue ubiqionone levels are subject to regulation by physiological factors that are related to the oxidative activity of the organism: they increase under the influence of oxidative stress, e.g. physical exercise, cold adaptation, thyroid hormone treatment, and decrease during aging. The specific aims of this proposal are: A) to ascertain the natural distribution and comprehensive pharmacokinetic parameters of ubiquinone(coenzyme Q10) and its regional distribution in the CNS; B) to search for one of the molecular links to neurodegeneration by studying the interaction among ubiquitin, ATP-dependent pathways, G actin, and neurofilaments in neurons; C) to test the effects of neuroprotectants such as selegiline on the striatal-, hippocampal-, and cortical levels of coenzyme Q10; D) to explore the antioxidant coregulation governing the status of Mn++ superoxide dismutase found in the mitochondria, Cu++, Zn++ superoxide dismutase located in the cytoplasm; and coenzyme Q10 found both in the mitochondria and cytoplasm; and E) to learn whether or not the administration of coenzyme Q10 could protect glial elements and neurons against neurotoxins such as MPTP causing Parkinsonism or NMDA- and non NMDA receptor activation causing excitatoxic disruption of Ca++ homeostasis and ensuing oxidative stress. The completion of these studies will undoubtedly provide additional items of information on reactive oxygen species-induced damage of mitochondrial DNA and the protective effects of coenzyme Q10(ubiquinol) to minimize it.