Chen Xiu-Cai, Tang Gui-Xue, Luo Wen-Hua, Shao Wen, Dai Jing, Zeng Shu-Tang, Huang Zhi-Shu, Chen Shuo-Bin, Tan Jia-Heng
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
J Am Chem Soc. 2021 Dec 15;143(49):20779-20791. doi: 10.1021/jacs.1c08860. Epub 2021 Dec 6.
The mitochondrial DNA G-quadruplex (mtDNA G4) is a potential regulatory element for the regulation of mitochondrial functions; however, its relevance and specific roles in diseases remain largely unknown. Here, we engineered a set of chemical probes, including , an mtDNA G4-specific fluorescent probe, together with , a mitochondria-targeted G4-stabilizing agent, to thoroughly investigate mtDNA G4s. Using to monitor previously intractable dynamics of mtDNA G4s, we surprisingly found that their formation was prevalent only in endothelial and cancer cells that rely on glycolysis for energy production. Consistent with this, promotion of mtDNA G4 folding by in turn caused glycolysis-related gene activation and glycolysis enhancement. Remarkably, this close relationship among mtDNA G4s, glycolysis, and cancer cells further allowed to accumulate in tumors and label them in vivo. Our work reveals an unprecedented link between mtDNA G4s and cell glycolysis, suggesting that mtDNA G4s may be a novel cancer biomarker and therapeutic target deserving further exploration.
线粒体DNA G-四链体（mtDNA G4）是调节线粒体功能的潜在调控元件；然而，其在疾病中的相关性和具体作用仍 largely未知。在此，我们设计了一组化学探针，包括一种mtDNA G4特异性荧光探针以及一种线粒体靶向的G4稳定剂，以全面研究mtDNA G4。使用该荧光探针监测此前难以捉摸的mtDNA G4动态变化，我们惊讶地发现，它们的形成仅在依赖糖酵解产生能量的内皮细胞和癌细胞中普遍存在。与此一致的是，该稳定剂促进mtDNA G4折叠进而导致糖酵解相关基因激活和糖酵解增强。值得注意的是，mtDNA G4、糖酵解和癌细胞之间的这种紧密关系进一步使得该稳定剂能够在肿瘤中积累并在体内标记肿瘤。我们的工作揭示了mtDNA G4与细胞糖酵解之间前所未有的联系，表明mtDNA G4可能是一种值得进一步探索的新型癌症生物标志物和治疗靶点。
