In cellular signaling, the diverse physiological actions of biological gases, including O₂, CO, NO, and H₂S, have attracted much interest. Hypoxia-inducible factors (HIFs), including HIF-1 and HIF-2, are transcription factors that respond to reduced intracellular O₂ availability. Polysulfides are substances containing varying numbers of sulfur atoms (H₂S_n) that are generated endogenously from H₂S by 3-mercaptopyruvate sulfurtransferase in the presence of O₂, and regulate ion channels, specific tumor suppressors, and protein kinases. However, the effect of polysulfides on HIF activation in hypoxic mammalian cells is largely unknown. Here, we have investigated the effect of polysulfide on cells in vitro. In established cell lines, polysulfide donors reversibly reduced cellular O₂ consumption and inhibited hypoxia-induced HIF-1α protein accumulation and the expression of genes downstream of HIFs; however, these effects were not observed in anoxia. In Von Hippel-Lindau tumor suppressor (VHL)- and mitochondria-deficient cells, polysulfides did not affect HIF-1α protein synthesis but destabilized it in a VHL- and mitochondria-dependent manner. For the first time, we show that polysulfides modulate intracellular O₂ homeostasis and regulate HIF activation and subsequent hypoxia-induced gene expression in a VHL- and mitochondria-dependent manner.

在细胞信号传导中，生物气体（包括 O ₂、CO、NO 和 H ₂ S）的多种生理作用引起了极大的兴趣。缺氧诱导因子 (HIF)，包括 HIF-1 和 HIF-2，是对细胞内 O ₂可用性降低作出反应的转录因子。多硫化物是含有不同数量的硫原子 (H ₂ S _{n ) 的物质，在 O 2}存在下由 3-巯基丙酮酸硫转移酶从 H ₂ S内源性产生，并调节离子通道、特定的肿瘤抑制因子和蛋白激酶。然而，多硫化物对缺氧哺乳动物细胞中 HIF 活化的影响在很大程度上是未知的。在这里，我们研究了多硫化物对体外细胞的影响。在已建立的细胞系中，多硫化物供体可逆地减少细胞 O ₂消耗并抑制缺氧诱导的 HIF-1α 蛋白积累和 HIF 下游基因的表达；然而，在缺氧中没有观察到这些影响。在 Von Hippel-Lindau 肿瘤抑制因子 (VHL) 和线粒体缺陷细胞中，多硫化物不影响 HIF-1α 蛋白合成，而是以 VHL 和线粒体依赖性方式使其不稳定。我们首次证明多硫化物可调节细胞内 O ₂稳态并以 VHL 和线粒体依赖性方式调节 HIF 激活和随后的缺氧诱导的基因表达。