Mitochondrial RelA empowers mtDNA G-quadruplex formation for hypoxia adaptation in cancer cells

Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regu...

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Bibliographic Details
Published inCell chemical biology
Main Authors Tang, Gui-Xue, Li, Mao-Lin, Zhou, Cui, Huang, Zhi-Shu, Chen, Shuo-Bin, Chen, Xiu-Cai, Tan, Jia-Heng
Format Journal Article
LanguageEnglish
Published United States 21.05.2024
Subjects
G-quadruplexes
NF-κB RelA
mitochondrial DNA
chemical genetic screen
energy metabolism
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Summary:Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming.
ISSN:2451-9448