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

Abstract

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 <b>MitoISCH</b>, an mtDNA G4-specific fluorescent probe, together with <b>MitoPDS</b>, a mitochondria-targeted G4-stabilizing agent, to thoroughly investigate mtDNA G4s. Using <b>MitoISCH</b> 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 <b>MitoPDS</b> in turn caused glycolysis-related gene activation and glycolysis enhancement. Remarkably, this close relationship among mtDNA G4s, glycolysis, and cancer cells further allowed <b>MitoISCH</b> 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.