Panagaki Theodora, Pecze Laszlo, Randi Elisa B, Nieminen Anni I, Szabo Csaba
Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Redox Biol. 2022 Sep;55:102416. doi: 10.1016/j.redox.2022.102416. Epub 2022 Jul 21.
Overexpression of the transsulfuration enzyme cystathionine-β-synthase (CBS), and overproduction of its product, hydrogen sulfide (HS) are recognized as potential pathogenetic factors in Down syndrome (DS). The purpose of the study was to determine how the mitochondrial function and core metabolic pathways are affected by DS and how pharmacological inhibition of CBS affects these parameters.
8 human control and 8 human DS fibroblast cell lines have been subjected to bioenergetic and fluxomic and proteomic analysis with and without treatment with a pharmacological inhibitor of CBS.
DS cells exhibited a significantly higher CBS expression than control cells, and produced more HS. They also exhibited suppressed mitochondrial electron transport and oxygen consumption and suppressed Complex IV activity, impaired cell proliferation and increased ROS generation. Inhibition of HS biosynthesis with aminooxyacetic acid reduced cellular HS, improved cellular bioenergetics, attenuated ROS and improved proliferation. C glucose fluxomic analysis revealed that DS cells exhibit a suppression of the Krebs cycle activity with a compensatory increase in glycolysis. CBS inhibition restored the flux from glycolysis to the Krebs cycle and reactivated oxidative phosphorylation. Proteomic analysis revealed no CBS-dependent alterations in the expression level of the enzymes involved in glycolysis, oxidative phosphorylation and the pentose phosphate pathway. DS was associated with the dysregulation of several components of the autophagy network; CBS inhibition normalized several of these parameters.
Increased HS generation in DS promotes pseudohypoxia and contributes to cellular metabolic dysfunction by causing a shift from oxidative phosphorylation to glycolysis.
转硫酶胱硫醚-β-合酶（CBS）的过表达及其产物硫化氢（HS）的过量产生被认为是唐氏综合征（DS）潜在的致病因素。本研究的目的是确定DS如何影响线粒体功能和核心代谢途径，以及CBS的药理抑制作用如何影响这些参数。
8个人类对照和成纤维细胞系及8个人类DS成纤维细胞系在使用或未使用CBS药理抑制剂处理的情况下，进行了生物能量学、通量组学和蛋白质组学分析。
DS细胞的CBS表达明显高于对照细胞，且产生更多的HS。它们还表现出线粒体电子传递和氧消耗受到抑制，复合体IV活性受到抑制，细胞增殖受损以及活性氧生成增加。用氨基氧乙酸抑制HS生物合成可降低细胞内HS水平，改善细胞生物能量学，减轻活性氧水平并促进增殖。13C葡萄糖通量组学分析显示，DS细胞的三羧酸循环活性受到抑制，糖酵解有代偿性增加。CBS抑制作用恢复了从糖酵解到三羧酸循环的通量，并重新激活了氧化磷酸化。蛋白质组学分析显示，参与糖酵解、氧化磷酸化和磷酸戊糖途径的酶的表达水平没有CBS依赖性改变。DS与自噬网络的几个成分失调有关；CBS抑制作用使其中一些参数恢复正常。
DS中HS生成增加会促进假性缺氧，并通过导致从氧化磷酸化向糖酵解的转变而导致细胞代谢功能障碍。
