Taylor Cormac T
UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Biochem J. 2008 Jan 1;409(1):19-26. doi: 10.1042/BJ20071249.
Mitochondrial respiration is responsible for more than 90% of oxygen consumption in humans. Cells utilize oxygen as the final electron acceptor in the aerobic metabolism of glucose to generate ATP which fuels most active cellular processes. Consequently, a drop in tissue oxygen levels to the point where oxygen demand exceeds supply (termed hypoxia) leads rapidly to metabolic crisis and represents a severe threat to ongoing physiological function and ultimately, viability. Because of the central role of oxygen in metabolism, it is perhaps not surprising that we have evolved an efficient and rapid molecular response system which senses hypoxia in cells, leading to the induction of an array of adaptive genes which facilitate increased oxygen supply and support anaerobic ATP generation. This response is governed by HIF (hypoxia-inducible factor). The oxygen sensitivity of this pathway is conferred by a family of hydroxylases which repress HIF activity in normoxia allowing its rapid activation in hypoxia. Because of its importance in a diverse range of disease states, the mechanism by which cells sense hypoxia and transduce a signal to the HIF pathway is an area of intense investigation. Inhibition of mitochondrial function reverses hypoxia-induced HIF leading to speculation of a role for mitochondria in cellular oxygen sensing. However, the nature of the signal between mitochondria and oxygen-sensing hydroxylase enzymes has remained controversial. In the present review, two models of the role for mitochondria in oxygen sensing will be discussed and recent evidence will be presented which raises the possibility that these two models which implicate ROS (reactive oxygen species) and oxygen redistribution respectively may complement each other and facilitate rapid and dynamic activation of the HIF pathway in hypoxia.
线粒体呼吸作用负责人体超过90%的氧气消耗。细胞在葡萄糖的有氧代谢过程中利用氧气作为最终电子受体来生成ATP，为大多数活跃的细胞过程提供能量。因此，组织氧水平下降到氧气需求超过供应的程度（称为缺氧）会迅速导致代谢危机，并对正在进行的生理功能乃至最终的生存能力构成严重威胁。由于氧气在新陈代谢中起着核心作用，我们进化出一种高效且快速的分子反应系统来感知细胞内的缺氧情况，从而诱导一系列适应性基因的表达，促进氧气供应增加并支持无氧ATP生成，这或许并不奇怪。这种反应由缺氧诱导因子（HIF）调控。该途径的氧敏感性由一类羟化酶赋予，这类羟化酶在常氧条件下抑制HIF活性，使其在缺氧时能快速激活。由于其在多种疾病状态中的重要性，细胞感知缺氧并向HIF途径传导信号的机制是一个深入研究的领域。线粒体功能的抑制可逆转缺氧诱导的HIF，这引发了关于线粒体在细胞氧感知中作用的推测。然而，线粒体与氧感知羟化酶之间信号的本质仍存在争议。在本综述中，将讨论线粒体在氧感知中作用的两种模型，并展示最近的证据，这些证据增加了以下可能性：分别涉及活性氧（ROS）和氧重新分布的这两种模型可能相互补充，并促进缺氧时HIF途径的快速和动态激活。
