Department of Medicine, Brigham and Women's Hospital, Boston, United States.
Department of Medicine, Harvard Medical School, Boston, United States.
Elife. 2023 Jul 10;12:e82597. doi: 10.7554/eLife.82597.
Hypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively in cancer cell models, comparatively little is known about how primary cell metabolism responds to hypoxia. Thus, we developed metabolic flux models for human lung fibroblast and pulmonary artery smooth muscle cells proliferating in hypoxia. Unexpectedly, we found that hypoxia decreased glycolysis despite activation of hypoxia-inducible factor 1α (HIF-1α) and increased glycolytic enzyme expression. While HIF-1α activation in normoxia by prolyl hydroxylase (PHD) inhibition did increase glycolysis, hypoxia blocked this effect. Multi-omic profiling revealed distinct molecular responses to hypoxia and PHD inhibition, and suggested a critical role for MYC in modulating HIF-1α responses to hypoxia. Consistent with this hypothesis, MYC knockdown in hypoxia increased glycolysis and MYC over-expression in normoxia decreased glycolysis stimulated by PHD inhibition. These data suggest that MYC signaling in hypoxia uncouples an increase in HIF-dependent glycolytic gene transcription from glycolytic flux.
缺氧需要代谢适应来维持能量需求高的细胞活动。虽然缺氧对癌细胞模型的代谢后果已经进行了广泛研究，但对于原代细胞代谢如何对缺氧做出反应，人们知之甚少。因此，我们为在缺氧条件下增殖的人肺成纤维细胞和肺动脉平滑肌细胞开发了代谢通量模型。出乎意料的是，我们发现尽管缺氧诱导因子 1α（HIF-1α）被激活并且糖酵解酶的表达增加，但缺氧会降低糖酵解。虽然脯氨酰羟化酶（PHD）抑制在常氧条件下通过激活 HIF-1α来增加糖酵解，但缺氧会阻断这种作用。多组学分析揭示了对缺氧和 PHD 抑制的不同分子反应，并表明 MYC 在调节 HIF-1α对缺氧的反应中起关键作用。与这一假设一致的是，在缺氧条件下敲低 MYC 会增加糖酵解，而在常氧条件下过表达 MYC 会减少 PHD 抑制刺激的糖酵解。这些数据表明，缺氧条件下的 MYC 信号转导将 HIF 依赖性糖酵解基因转录的增加与糖酵解通量解耦。
