Choksi Kashyap B, Papaconstantinou John
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0643, USA.
Free Radic Biol Med. 2008 May 15;44(10):1795-805. doi: 10.1016/j.freeradbiomed.2008.01.032. Epub 2008 Feb 13.
Mitochondrially generated ROS increase with age and are a major factor that damages proteins by oxidative modification. Accumulation of oxidatively damaged proteins has been implicated as a causal factor in the age-associated decline in tissue function. Mitochondrial electron transport chain (ETC) complexes I and III are the principle sites of ROS production, and oxidative modifications to their complex subunits inhibit their in vitro activity. We hypothesize that mitochondrial complex subunits may be primary targets for modification by ROS, which may impair normal complex activity. This study of heart mitochondria from young, middle-aged, and old mice reveals that there is an age-related decline in complex I and V activity that correlates with increased oxidative modification to their subunits. The data also show a specificity for modifications of the ETC complex subunits, i.e., several proteins have more than one type of adduct. We postulate that the electron leakage from ETC complexes causes specific damage to their subunits and increased ROS generation as oxidative damage accumulates, leading to further mitochondrial dysfunction, a cyclical process that underlies the progressive decline in physiologic function of the aged mouse heart.
线粒体产生的活性氧（ROS）随年龄增长而增加，是通过氧化修饰损害蛋白质的主要因素。氧化损伤蛋白质的积累被认为是组织功能随年龄下降的一个因果因素。线粒体电子传递链（ETC）复合体I和III是ROS产生的主要部位，对其复合亚基的氧化修饰会抑制其体外活性。我们假设线粒体复合亚基可能是ROS修饰的主要靶点，这可能会损害正常的复合体活性。这项对年轻、中年和老年小鼠心脏线粒体的研究表明，复合体I和V的活性存在与年龄相关的下降，这与它们亚基氧化修饰的增加相关。数据还显示了ETC复合亚基修饰的特异性，即几种蛋白质有不止一种加合物类型。我们推测，ETC复合体的电子泄漏会对其亚基造成特异性损伤，并随着氧化损伤的积累而增加ROS的产生，导致进一步的线粒体功能障碍，这是一个循环过程，是老年小鼠心脏生理功能逐渐下降的基础。
