Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate.
Suppressing Mitochondrial Respiration Is Critical for Hypoxia Tolerance in the Fetal Growth Plate.
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DOI：
10.1016/j.devcel.2019.04.029
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发表时间：
2019-06
影响因子：
11.8
通讯作者：
Qing Yao;M. Khan;C. Merceron;Edward L LaGory;Zachary Tata;L. Mangiavini;Jiarui Hu;Krishna G. Vemulapalli;N. Chandel;A. Giaccia;E. Schipani
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文献类型：
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作者：
Qing Yao;M. Khan;C. Merceron;Edward L LaGory;Zachary Tata;L. Mangiavini;Jiarui Hu;Krishna G. Vemulapalli;N. Chandel;A. Giaccia;E. Schipani
氧（O2）既是不可缺少的代谢底物，也是控制缺氧诱导因子1α (Hif1a)活性的调节信号，Hif1a是细胞适应低氧张力（缺氧）的介质。缺氧细胞需要Hif1a才能存活。此外，Hif1a是线粒体呼吸的抑制剂。因此，我们假设增强线粒体呼吸对体内缺氧细胞的存活是有害的。我们在缺氧的胎儿生长板中测试了这个假设。我们的研究结果表明，线粒体呼吸对于生长板软骨细胞的存活是必不可少的。此外，在缺乏Hif1a的生长板中观察到，它的损伤可以防止极度缺氧和大量软骨细胞死亡。因此，增加线粒体呼吸至少在一定程度上通过增加细胞内缺氧影响缺氧软骨细胞的存活。因此，我们提出线粒体呼吸的部分抑制在发育过程中是至关重要的，以保护生理缺氧的组织免受致命的细胞内缺氧。
Oxygen (O2) is both an indispensable metabolic substrate and a regulatory signal that controls the activity of Hypoxia-Inducible Factor 1α (Hif1a), a mediator of the cellular adaptation to low O2tension (hypoxia). Hypoxic cells require Hif1a to survive. Additionally, Hif1a is an inhibitor of mitochondrial respiration. Hence, we hypothesized that enhancing mitochondrial respiration is detrimental to the survival of hypoxic cellsin vivo. We tested this hypothesis in the fetal growth plate, which is hypoxic. Our findings show that mitochondrial respiration is dispensable for survival of growth plate chondrocytes. Furthermore, its impairment prevents the extreme hypoxia and the massive chondrocyte death observed in growth plates lacking Hif1a. Consequently, augmenting mitochondrial respiration affects the survival of hypoxic chondrocytes by, at least in part, increasing intracellular hypoxia. We thus propose that partial suppression of mitochondrial respiration is crucial during development to protect the tissues that are physiologically hypoxic from lethal intracellular anoxia.