Sgarbi G, Gorini G, Costanzini A, Barbato S, Solaini G, Baracca A
Department of Biomedical and Neuromotor Sciences, Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, via Irnerio, 48, 40126 Bologna, Italy.
Department of Biomedical and Neuromotor Sciences, Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, via Irnerio, 48, 40126 Bologna, Italy.
Int J Biochem Cell Biol. 2017 Jul;88:133-144. doi: 10.1016/j.biocel.2017.05.005. Epub 2017 May 5.
We have previously demonstrated that cells adapt to hypoxia using different metabolic reprogramming mechanisms depending on metabolism. We now investigate how the different adapting mechanisms affect reactive oxygen species (ROS) levels, and how ROS levels and cellular metabolism are linked. We show that when skin fibroblasts grew under short-term hypoxia (1% oxygen tension) ROS level markedly decreased (-50%) whatever substrate was available to the cells. Indeed, cellular ROS level linearly and directly decreased with oxygen tension. However, these relationships cannot explain the progressive ROS level decrease observed after prolonged cells hypoxia exposure. In glucose-enriched medium reduced mitochondrial mass and greater fragmentation are observed, both clear-cut indications of mitophagy suggesting that this is responsible for cellular ROS level decrease. Otherwise, in glucose-free medium exposure to prolonged hypoxia resulted in only minor mass reduction, but significantly enhanced expression of antioxidant enzymes. Interestingly, cellular ROS levels were lower in glucose-free compared to glucose-enriched medium under either normoxic or hypoxic conditions. Taken together, these findings reveal that in primary human fibroblasts hypoxia induces a decline in ROS and that different metabolism-dependent mechanisms contribute it, besides the major oxygen concentration decrease. In addition, the present data support the notion that metabolisms generating fewer ROS are associated with lower HIF-1α stabilization.
我们之前已经证明，细胞根据代谢情况使用不同的代谢重编程机制来适应缺氧。我们现在研究不同的适应机制如何影响活性氧（ROS）水平，以及ROS水平与细胞代谢是如何关联的。我们发现，当皮肤成纤维细胞在短期缺氧（氧张力为1%）条件下生长时，无论细胞可用何种底物，ROS水平都会显著降低（-50%）。事实上，细胞ROS水平与氧张力呈线性直接下降关系。然而，这些关系无法解释细胞长时间暴露于缺氧环境后观察到的ROS水平的逐渐降低。在富含葡萄糖的培养基中，观察到线粒体质量减少和碎片化加剧，这两者都是线粒体自噬的明确迹象，表明这是细胞ROS水平降低的原因。否则，在无葡萄糖培养基中长时间暴露于缺氧环境仅导致轻微的质量减少，但抗氧化酶的表达显著增强。有趣的是，在常氧或缺氧条件下，无葡萄糖培养基中的细胞ROS水平均低于富含葡萄糖的培养基。综上所述，这些发现揭示了在原代人成纤维细胞中，缺氧会导致ROS水平下降，除了主要的氧浓度降低外，不同的代谢依赖机制也对此有贡献。此外，目前的数据支持这样一种观点，即产生较少ROS的代谢与较低的HIF-1α稳定性相关。
