Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Cell Signal. 2017 Oct;38:230-237. doi: 10.1016/j.cellsig.2017.07.008. Epub 2017 Jul 12.
The adaptive response to hypoxia is mediated in large part by stabilization of the hypoxia-inducible factors, HIF-1α and HIF-2α. A hallmark of this response is the metabolic shift to decreased oxidative phosphorylation and increased glycolysis. We hypothesized that hypoxic responses would include a suppression of mitochondrial gene expression. We determined the effects of hypoxia on TFAM, a key mitochondrial transcription factor, in normal pulmonary artery endothelial cells. Hypoxia decreased gene expression of TFAM and that of its upstream regulator, the transcriptional co-activator PGC1β. Although HIF-1α and HIF-2α pathways both contributed to hypoxia-mediated PGC1β suppression, TFAM suppression was regulated solely by HIF-2α-dependent mechanisms. We found that HIF-2α suppresses TFAM by decreasing c-Myc expression. In addition, we show a role for c-Jun in this pathway, linking HIF-2α with attenuation of c-Jun activation. Taken together, these findings establish a new link between HIF-2α and MAPK-signaling that mediates the adaptive regulation of mitochondrial gene expression under low oxygen tension.
缺氧的适应反应在很大程度上是通过稳定缺氧诱导因子 HIF-1α 和 HIF-2α 来介导的。这种反应的一个标志是代谢向氧化磷酸化减少和糖酵解增加的转变。我们假设缺氧反应将包括对线粒体基因表达的抑制。我们在正常肺动脉内皮细胞中确定了缺氧对 TFAM（一种关键的线粒体转录因子）的影响。缺氧降低了 TFAM 的基因表达及其上游调节因子转录共激活因子 PGC1β 的基因表达。虽然 HIF-1α 和 HIF-2α 通路都有助于缺氧介导的 PGC1β 抑制，但 TFAM 的抑制仅受 HIF-2α 依赖机制的调节。我们发现 HIF-2α 通过降低 c-Myc 表达来抑制 TFAM。此外，我们在该途径中发现了 c-Jun 的作用，将 HIF-2α 与 c-Jun 激活的衰减联系起来。总之，这些发现建立了 HIF-2α 和 MAPK 信号之间的新联系，介导了在低氧张力下线粒体基因表达的适应性调节。
