Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria; Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.
Biochim Biophys Acta Bioenerg. 2021 Jun 1;1862(6):148393. doi: 10.1016/j.bbabio.2021.148393. Epub 2021 Feb 5.
Cancer cells bioenergetics is more dependent on glycolysis than mitochondrial oxidative phosphorylation, a phenomenon known as the Warburg Effect. It has been proposed that inhibition of glycolysis may selectively affect cancer cells. However, the effects of glycolysis inhibition on mitochondrial function and structure in cancer cells are not completely understood. Here, we investigated the comparative effects of 2-deoxy-d-glucose (2-DG, a glucose analogue, which suppresses cellular glycolysis) on cellular bioenergetics in human colon cancer DLD-1 cells, smooth muscle cells, human umbilical vein endothelial cells and HL-1 cardiomyocytes. In all cells, 2-DG treatment resulted in significant ATP depletion, however, the cell viability remained unchanged. Also, we did not observe the synergistic effects of 2-DG with anticancer drugs doxorubicin and 5-fluorouracil. Instead, after 2-DG treatment and ATP depletion, mitochondrial respiration and membrane potential were significantly enhanced and mitochondrial morphology changed in the direction of more network organization. Analysis of protein expression demonstrated that 2-DG treatment induced an activation of AMPK (elevated pAMPK/AMPK ratio), increased mitochondrial fusion (mitofusins 1 and 2) and decreased fission (Drp1) proteins. In conclusion, this study suggests a strong link between respiratory function and structural organization of mitochondria in the cell. We propose that the functionality of the mitochondrial network is enhanced compared to disconnected mitochondria.
癌细胞的生物能量学比线粒体氧化磷酸化更依赖于糖酵解，这种现象被称为瓦博格效应。有人提出，抑制糖酵解可能会选择性地影响癌细胞。然而，糖酵解抑制对癌细胞中线粒体功能和结构的影响尚不完全清楚。在这里，我们研究了 2-脱氧-D-葡萄糖（2-DG，一种抑制细胞糖酵解的葡萄糖类似物）对人结肠癌细胞 DLD-1 细胞、平滑肌细胞、人脐静脉内皮细胞和 HL-1 心肌细胞细胞生物能量的比较影响。在所有细胞中，2-DG 处理导致显著的 ATP 耗竭，但细胞活力保持不变。此外，我们没有观察到 2-DG 与抗癌药物阿霉素和 5-氟尿嘧啶的协同作用。相反，在 2-DG 处理和 ATP 耗竭后，线粒体呼吸和膜电位显著增强，线粒体形态向更网络化的方向变化。蛋白表达分析表明，2-DG 处理诱导 AMPK 激活（升高的 pAMPK/AMPK 比值），增加线粒体融合（线粒体融合蛋白 1 和 2），减少分裂（Drp1）蛋白。总之，这项研究表明细胞中线粒体呼吸功能和结构组织之间存在很强的联系。我们提出，与不连接的线粒体相比，线粒体网络的功能得到了增强。
