Unifying theory of hypoxia tolerance: Molecular metabolic defense and rescue mechanisms for surviving oxygen lack
Unifying theory of hypoxia tolerance: Molecular metabolic defense and rescue mechanisms for surviving oxygen lack
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DOI：
10.1073/pnas.93.18.9493
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发表时间：
1996-09-03
影响因子：
11.1
通讯作者：
Land, SC
中科院分区：
文献类型：
--
作者：
Hochachka, PW;Buck, LT;Land, SC
我们发展了一个统一的理论缺氧耐受性的基础上的信息从两个细胞水平的模型本文通过对高耐缺氧水龟脑皮层细胞和离体肝细胞的比较，以及对缺氧敏感系统的比较，认为耐缺氧系统对缺氧的反应分为两个阶段缺氧的第一道防线包括ATP需求和ATP供应途径的平衡抑制;这种调节使腺苷酸稳定在新的稳态水平，即使ATP周转率大大下降。离子泵的ATP需求通过肝细胞中的广义“通道"阻滞和神经元中的”尖峰"阻滞而下调。蛋白质合成的低ATP需求可能通过翻译停滞而下调。在缺氧敏感细胞中，这种翻译停滞似乎是不可逆的，但如果通过优先调节几种蛋白质的表达来延长缺氧时间，则耐缺氧系统激活“拯救"机制。在这些细胞中，支持缺氧救援和防御的级联过程始于氧传感器（血红素蛋白）和信号转导通路，这导致了显著的基于基因的代谢重编程-救援过程-在整个缺氧期间维持代谢中能量需求和能量供应通路的下调。这项最近的工作开始阐明常氧维持ATP周转率如何被大幅（10倍）下调至新的低代谢稳态，这是长期缺氧或缺氧生存的先决条件。这些发展的影响在生物学和医学方面是广泛的。
We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and from other more hypoxia sensitive systems, We propose that the response of hypoxia tolerant systems to oxygen lack occurs in two phases (defense and rescue), The first lines of defense against hypoxia include a balanced suppression of ATP-demand and ATP-supply pathways; this regulation stabilizes (adenylates) at new steady-state levels even while ATP turnover rates greatly decline. The ATP demands of ion pumping are down-regulated by generalized ''channel'' arrest in hepatocytes and by ''spike'' arrest in neurons. Hypoxic ATP demands of protein synthesis are down-regulated probably by translational arrest. In hypoxia sensitive cells this translational arrest seems irreversible, but hypoxia-tolerant systems activate ''rescue'' mechanisms if the period of oxygen lack is extended by preferentially regulating the expression of several proteins. In these cells, a cascade of processes underpinning hypoxia rescue and defense begins with an oxygen sensor (a heme protein) and a signal-transduction pathway, which leads to significant gene-based metabolic reprogramming-the rescue process-with maintained down-regulation of energy-demand and energy-supply pathways in metabolism throughout the hypoxic period. This recent work begins to clarify how normoxic maintenance ATP turnover rates can be drastically (10-fold) down regulated to a new hypometabolic steady state, which is prerequisite for surviving prolonged hypoxia or anoxia. The implications of these developments are extensive in biology and medicine.