Monitoring and Modulating mtDNA G‑Quadruplex Dynamics Reveal Its Close Relationship to Cell Glycolysis

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 MitoISCH, an mtDNA G4-specific fluoresc...

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Published inJournal of the American Chemical Society Vol. 143; no. 49; pp. 20779 - 20791
Main Authors 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
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 15.12.2021
Amer Chemical Soc
Subjects
3T3 Cells
Animals
Cell Line, Tumor
Chemistry
Chemistry, Multidisciplinary
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Endothelial Cells - metabolism
Fluorescent Dyes - chemistry
G-Quadruplexes
Glycolysis - physiology
Humans
Mice
Mice, Nude
Mitochondria - metabolism
Physical Sciences
Science & Technology
VISUALIZATION
HIF-1
TUMOR PROGRESSION
DNA
MITOCHONDRIA
TERMINATION
HALLMARKS
HYPOXIA
CANCER
PROBE
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Summary: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 MitoISCH, an mtDNA G4-specific fluorescent probe, together with MitoPDS, a mitochondria-targeted G4-stabilizing agent, to thoroughly investigate mtDNA G4s. Using MitoISCH 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 MitoPDS in turn caused glycolysis-related gene activation and glycolysis enhancement. Remarkably, this close relationship among mtDNA G4s, glycolysis, and cancer cells further allowed MitoISCH 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.
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ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.1c08860