Chandel N S, Schumacker P T
The University of Chicago, Pulmonary and Critical Care Medicine, Chicago, Illinois 60637, USA.
J Appl Physiol (1985). 2000 May;88(5):1880-9. doi: 10.1152/jappl.2000.88.5.1880.
Hypoxia elicits a variety of adaptive responses at the tissue level, at the cellular level, and at the molecular level. A physiological response to hypoxia requires the existence of an O(2) sensor coupled to a signal transduction system, which in turn activates the functional response. Although much has been learned about the signaling systems activated by hypoxia, no consensus exists regarding the nature of the underlying O(2) sensor or whether multiple sensors exist. Among previously considered mechanisms, heme proteins have been suggested to undergo allosteric modification in response to O(2) binding or release at different PO(2) levels. Other studies suggest that ion channels may change conductance as a function of PO(2), allowing them to signal the onset of hypoxia. Still other studies suggest that NADPH oxidase may decrease its generation of reactive O(2) species (ROS) during hypoxia. Recent data suggest that mitochondria may function as O(2) sensors by increasing their generation of ROS during hypoxia. These oxidant signals appear to act as second messengers in the adaptive responses to hypoxia in a variety of cell types. Such observations contribute to a growing awareness that mitochondria do more than just generate ATP, in that they initiate signaling cascades involved in adaptive responses to hypoxia and that they participate in the control of cell death pathways.
缺氧会在组织水平、细胞水平和分子水平引发多种适应性反应。对缺氧的生理反应需要存在一个与信号转导系统相连的O₂传感器，该信号转导系统进而激活功能反应。尽管关于缺氧激活的信号系统已经有了很多了解，但对于潜在的O₂传感器的性质或是否存在多个传感器尚无共识。在先前考虑的机制中，有人提出血红素蛋白会在不同的PO₂水平下响应O₂的结合或释放而发生变构修饰。其他研究表明，离子通道可能会根据PO₂改变其电导，使其能够发出缺氧开始的信号。还有其他研究表明，NADPH氧化酶在缺氧期间可能会减少其活性氧（ROS）的生成。最近的数据表明，线粒体可能通过在缺氧期间增加ROS的生成而作为O₂传感器发挥作用。这些氧化信号似乎在多种细胞类型对缺氧的适应性反应中充当第二信使。此类观察结果使人们越来越意识到，线粒体的作用不止于产生ATP，它们还启动参与对缺氧适应性反应的信号级联反应，并且参与细胞死亡途径的控制。
