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Updated: Jun 4, 2026

Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals
05:59

Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals

Published on: May 19, 2023

Do G4 ligands induce mitochondrial dysfunction without ROS induction

Xinru Zhang1,2, Fei Li1, Siyi Zeng1

  • 1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Iscience
|June 3, 2026
PubMed

Insights

G-quadruplex (G4) DNA ligands target cancer cells by disrupting mitochondrial function without causing reactive oxygen species (ROS) bursts. This selective G4 targeting offers a novel anticancer strategy with reduced toxicity.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genomics

Background:

  • G-quadruplex (G4) DNA structures are increasingly recognized as promising therapeutic targets due to their presence in nuclear and mitochondrial genomes.
  • Understanding the cellular effects of G4 ligands is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To develop and utilize a mitochondrial high-content profiling platform (Mito-HiCP) to compare the effects of G4 ligands and cisplatin on cancer and normal cells.
  • To elucidate the mechanism of action of G4 ligands, particularly their impact on mitochondrial function and reactive oxygen species (ROS) production.

Main Methods:

  • Development of the Mito-HiCP platform integrating automated microscopy and quantitative image analysis.
  • Comparative analysis of G4 ligands (including 360 A and its isomer EDL21) and cisplatin in various cell types.
  • Assessment of mitochondrial membrane potential, ROS levels, mitochondrial DNA copy number, transcription, and electron transport chain protein expression.

Main Results:

  • G4 ligands induce mitochondrial depolarization without ROS bursts, unlike cisplatin which is associated with ROS.
  • The G4 ligand 360 A selectively reduces ROS levels in both mitochondria and cytosol and demonstrates tumor selectivity.
  • 360 A's isomer (EDL21), which does not bind G4 DNA, showed no significant effect, confirming a G4-dependent mechanism.
  • Mechanistically, 360 A decreases mitochondrial DNA copy number, transcription, and electron transport chain protein levels.
  • G4 targeting was shown to uncouple mitochondrial membrane potential from ROS production.

Conclusions:

  • G4 ligands represent a distinct class of anticancer agents that target mitochondria selectively.
  • The developed Mito-HiCP platform is effective for dissecting mitochondrial responses and redox regulation.
  • G4 targeting offers a novel mode of redox regulation for selective anticancer activity, distinct from ROS-inducing chemotherapies.
Keywords:
Biochemistrycell biologymolecular biology

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