Mitochondrial fuction, oxidative damage, and aging

线粒体功能、氧化损伤和衰老

• 批准号: 7022219
• 负责人: David J. Marcinek
• 金额: $ 10.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022219
• 关键词: aging; catalase; enzyme biosynthesis; exercise; genetically modified animals; laboratory mouse; mitochondria; muscle metabolism; oxidative phosphorylation; oxidative stress; oxygen consumption; spectrometry; striated muscles

DESCRIPTION (provided by applicant): The mitochondrial theory of aging states that the accumulation of oxidative damage with age results in mitochondrial dysfunction, leading to altered energetics and initiation of cell death cascades. However, support for this chain of events is equivocal, despite several decades of intense research effort. Due to the lack of necessary tools to measure mitochondrial function in vivo, current approaches have typically focused on in vitro measurements of mitochondrial function, particularly the electron transport chain (ETC), making it necessary to extrapolate to the physiological state. To overcome this limitation, we have developed novel methods to directly measure mitochondrial function in vivo. We propose that reduced coupling of ATP synthesis to O2 consumption (P/O) is an important mechanism of mitochondrial dysfunction in aging muscle. We test this hypothesis in aim 1 by determining in vivo mitochondrial P/O, maximal ETC flux, capacity for ATP synthesis, and in vitro ETC activity in relation to the accumulation of oxidative damage in mouse skeletal muscle at four ages. In aim 2 we test the mechanistic link between oxidative damage and mitochondrial dysfunction in vivo using a transgenic mouse model that overexpresses an antioxidant enzyme in mitochondria to increase the resistance of mitochodnria to oxidative stress with age. Aim 3 tests the reversibility of the loss of mitochondrial function in aging muscle using exercise training to increase mitochondrial proliferation and turnover, thereby replacing damaged mitochondria. This proposal uses state of the art in vivo spectroscopy to address the controversy surrounding experimental evidence for the mitochondrial theory of aging. This mentored research plan will facilitate Dr. Marcinek's development as a gerontologic researcher and junior faculty member in the Department of Radiology at the University of Washington. The mentors for this proposal represent several decades of experience in their respective fields - George Martin and Peter Rabinovitch for the biology of aging and Kevin Conley and Martin Kushmerick for quantitative bioenergetics and in vivo spectroscopy. Internationally recognized programs in muscle metabolism and the biology of aging at the University of Washington make this environment ideally suited to a research career integrating the study of aging and metabolism.

描述（由申请人提供）：衰老的线粒体理论指出，氧化损伤与年龄的积累会导致线粒体功能障碍，从而导致能量学和启动细胞死亡级联反应。但是，尽管数十年的激烈研究工作，但对这一事件链的支持仍然是模棱两可的。由于缺乏在体内测量线粒体功能的必要工具，因此当前的方法通常集中在线粒体功能的体外测量上，尤其是电子传输链（ETC），因此必须将其推断到生理状态。为了克服这一局限性，我们开发了新的方法来直接测量体内线粒体功能。我们建议减少ATP合成与O2消耗（P/O）的偶联是衰老肌肉中线粒体功能障碍的重要机制。 我们通过确定体内线粒体p/o，最大ECT通量，ATP合成的能力以及与四个年龄段小鼠骨骼肌氧化损伤的积累有关，我们在AIM 1中检验了这一假设。在AIM 2中，我们使用转基因小鼠模型在体内测试体内氧化损伤与线粒体功能障碍之间的机理联系，该模型过表达线粒体中的抗氧化剂酶，以提高线粒体对氧化应激的耐药性。 AIM 3测试了使用运动训练在衰老肌肉中丧失线粒体功能的可逆性，以增加线粒体增殖和周转，从而取代线粒体受损。该提议利用体内光谱中的艺术状态来解决围绕线粒体衰老理论的实验证据的争议。这项指导的研究计划将促进Marcinek博士作为华盛顿大学放射学系的老年学研究人员和初级教职员工的发展。该提案的导师代表了各自领域的数十年经验 - 乔治·马丁（George Martin）和彼得·拉比诺维奇（Peter Rabinovitch）的衰老生物学，凯文·康利（Kevin Conley）和马丁·库什梅里克（Martin Kushmerick），用于定量生物能学和体内光谱学。华盛顿大学的国际肌肉代谢和衰老生物学方面的国际认可的计划使这种环境非常适合整合衰老和代谢研究的研究生涯。