Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia.
Monash Health, Melbourne, VIC 3186, Australia.
Int J Mol Sci. 2021 Feb 19;22(4):2046. doi: 10.3390/ijms22042046.
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle ( = 1.03 × 10), the pentose phosphate pathway ( = 0.034, G6PD = 5.5 × 10), mitochondrial fatty acid β-oxidation ( = 9.2 × 10), and degradation of amino acids including glutamine/glutamate (GLS = 0.034, GLUD1 = 0.048, GOT2 = 0.026), branched-chain amino acids (BCKDHA = 0.028, BCKDHB = 0.031) and essential amino acids (FAH = 0.036, GCDH = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.
虽然对肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）的生物医学基础的理解正在不断加深，但潜在的病理机制仍不确定。我们最近报告称，ME/CFS 患者来源的淋巴母细胞系中由于复合物 V 导致的基础氧消耗减少，这表明线粒体呼吸效率低下。这伴随着呼吸能力的升高、哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号活性的升高以及参与三羧酸（TCA）循环、脂肪酸β-氧化和线粒体转运的酶的表达升高。这些和其他观察结果使我们假设为线粒体提供可氧化底物的途径失调。在我们目前的研究中，我们旨在通过应用全细胞转录组学、蛋白质组学和能量应激信号活性测量的组合，重新研究这一假设，该组合使用了我们不断增长的文库中多达 34 个 ME/CFS 和 31 个健康对照淋巴母细胞系的子集。虽然根据我们之前观察到的不变糖酵解率，糖酵解酶的水平没有变化，但 ME/CFS 淋巴母细胞的全细胞蛋白质组含有升高水平的 TCA 循环（ = 1.03 × 10）、戊糖磷酸途径（ = 0.034，G6PD = 5.5 × 10）、线粒体脂肪酸β-氧化（ = 9.2 × 10）和包括谷氨酰胺/谷氨酸（GLS = 0.034，GLUD1 = 0.048，GOT2 = 0.026）、支链氨基酸（BCKDHA = 0.028，BCKDHB = 0.031）和必需氨基酸（FAH = 0.036，GCDH = 0.006）在内的氨基酸的降解。主要细胞能量应激传感器 AMPK 的活性升高，但增加未达到统计学意义。结果表明，ME/CFS 代谢失调，使得替代糖酵解的途径比对照更广泛地被利用，以为线粒体提供可氧化的底物。
Zotero 插件
