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Nearly all the energy used by cells comes from the bonds that make up complex organic compounds. These organic compounds are broken down into simpler molecules, such as glucose. As a result, cells extract energy from glucose over many chemical reactions—a process called cellular respiration.
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Exploring Mitochondrial Energy Metabolism of Single 3D Microtissue Spheroids Using Extracellular Flux Analysis
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Ambigols Uncouple Oxidative Phosphorylation In Vitro.

Valerie I C Rebhahn1, Clemens A Wolf2, Timo H J Niedermeyer1

  • 1Institute of Pharmacy, Pharmaceutical Biology, Freie Universität Berlin, Berlin 14195, Germany.

ACS Chemical Biology
|April 2, 2026
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Summary
This summary is machine-generated.

Ambigols A and C from cyanobacteria uncouple oxidative phosphorylation, dissipating membrane potential in both bacterial and human cells. This finding explains their broad bioactivity and suggests potential for new antibiotic development.

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Area of Science:

  • Biochemistry
  • Microbiology
  • Pharmacology

Background:

  • Ambigols are natural products from *Symphyonema bifilamentata* with a broad bioactivity spectrum.
  • Ambigols A and C are investigated for potential applications, including new antibiotic development.
  • The precise mode of action for ambigols remained largely unknown.

Purpose of the Study:

  • To elucidate the mode of action of ambigols A and C.
  • To investigate the effects of ambigols on cellular bioenergetics.
  • To determine if ambigols target membrane potential in prokaryotic and eukaryotic cells.

Main Methods:

  • Assessing the effect of ambigols A and C on oxidative phosphorylation in HeLa cells.
  • Measuring mitochondrial membrane potential dissipation.
  • Quantifying oxygen consumption rates.
  • Evaluating the impact on the membrane potential of Gram-negative bacteria.

Main Results:

  • Ambigols A and C were identified as uncouplers of oxidative phosphorylation.
  • These compounds dissipate the mitochondrial membrane potential in HeLa cells.
  • Ambigols A and C increase the oxygen consumption rate in HeLa cells.
  • The membrane potential of Gram-negative bacteria is also targeted by ambigols.

Conclusions:

  • The broad bioactivity of ambigols is attributed to their uncoupling effect on oxidative phosphorylation.
  • Ambigols disrupt the electrochemical membrane potential in both prokaryotic and eukaryotic cells, indicating unspecific uncoupler effects.
  • These findings provide a foundation for understanding ambigols' bioactivity and guide future development of ambigol-based therapeutics.