Caveolae as capacitors for oxygen

摘要 不同物种的生物寿命差异很大：线虫的寿命为14-25天，老鼠的寿命为几天 人类平均可以活到80多岁，而像巨蚌这样的生物可以活到500岁以上 好几年了。在衰退的年轻人中，可能存在调节细胞功能效率的保守机制 随着年龄的增长，最终导致全身和器官衰竭和死亡。尽管有大量的 已经提出的解释随着生物体衰老而丧失效率和功能的想法，不是 进化保守的衰老的共同综合理论已经被提出，因此，代表了 知识上的重大鸿沟。氧悖论突显了一个谜团，即氧气是一种对 新陈代谢的生命机器，但对居住在这个星球上的所有形式的生命都是有毒的。这一悖论的关键是 两个简单但生物学上基本的氧化还原反应：第一个反应，本质上与 光合作用的水分裂，标志着真核生物的黎明，在这个过程中线粒体‘呼吸’氧气到 酶促质子梯度催化氧化磷酸化和第二反应 过量的物质被消耗以产生导致损害的活性物质。最大限度地提高第一反应 最大限度地减少第二，在严格控制下保持氧气水平所需的寿命。有议员建议， 对这一悖论的进化反应是在细胞膜内产生胆固醇，作为一种“驯服”氧气的方式 并允许将其作为一种能源和作为连接膜和 新陈代谢。我们假设小窝蛋白，一种将胆固醇组织成膜的支架蛋白 微域，作为一个“电容器”存在，通过调节 随着年龄的增长，膜氧和小窝蛋白在某些器官的表达减少，从而导致 氧气毒性增加。我们进一步提出，这种毒性可以通过重新表达小窝蛋白来限制。 高龄的设定。将研究以下具体目标：具体目标1：确定什么 洞穴的某些方面可用作膜氧电容器。具体目标2：确定年龄和年龄的影响 小窝蛋白表达对器官储氧能力和毒性的影响。

ABSTRACT The life span of organisms differs widely among species: C. elegans live 14-25 days, mice for a couple of years, humans into their eighties on average, and organisms such as the giant clam can live upwards of 500 years. There are likely conserved mechanisms that regulate the efficiency of cell function in youth that declines with age, ultimately resulting in systemic and organismal failure and death. In spite of the large number of ideas that have been proposed to account for the loss in efficiency and function as an organism ages, no common integrative theory for aging that is evolutionarily conserved has been advanced and thus, represents a major gap in knowledge. The oxygen paradox highlights the mystery that O2 is so critical a fuel for the metabolic machinery of life, yet so toxic to all forms of life inhabiting this planet. The key to this paradox are the two simple, yet biologically fundamental redox reactions: the first reaction, which is essentially the reverse of photosynthetic water splitting, marks the dawn of eucarya in which mitochondria `respire' oxygen to enzymatically generate proton gradient fueling oxidative phosphorylation and the second reaction where O2 in excess is consumed to generate reactive species that induce damage. To maximize the first reaction and minimize the second, life needed to maintain oxygen levels under tight control. It has been proposed that the evolutionary response to this paradox was to create cholesterol within membranes as a way to “tame” oxygen and allow for its biologic use as an energy source and as a primary feature that links membranes and metabolism. We hypothesize that caveolin, a scaffolding protein that organizes cholesterol into membrane microdomains, exists as a “capacitor” to create the efficiency of metabolism in youth through regulation of membrane oxygen and that with aging, caveolin expression is decreased in certain organs, thereby leading to increased oxygen toxicity. We further propose that this toxicity can be limited by re-expression of caveolin in the setting of advanced age. The following specific aims will be studies: Specific Aim 1: Determine what aspects of caveolin serve as membrane oxygen capacitors. Specific Aim 2: Determine the impact of age and caveolin expression on organ oxygen storage capacity and toxicity.