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The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on

Esther M Gottwald1, Claus D Schuh1, Patrick Drücker2

  • 1Institute of Anatomy, University of Zurich, Zurich, Switzerland.

Scientific Reports
|February 2, 2020
PubMed

Insights

The iron chelator Deferasirox (DFX) causes severe organ toxicity by inducing mitochondrial swelling. This occurs due to increased proton permeability of the inner mitochondrial membrane, an off-target effect not seen with other iron chelators.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Toxicology

Background:

  • Deferasirox (DFX) is an iron chelator used clinically.
  • DFX causes severe, unexplained toxicity in patients.
  • Mitochondrial dysfunction is implicated in various toxicities.

Purpose of the Study:

  • To elucidate the mechanism behind Deferasirox-induced toxicity.
  • To investigate the effects of DFX on mitochondria in vivo and in vitro.
  • To determine if DFX's effects are specific to its iron-chelating properties.

Main Methods:

  • In vivo kidney toxicity model.
  • Live cell imaging.
  • In vitro biophysical models.
  • Mitochondrial function assays.

Main Results:

  • DFX causes partial mitochondrial uncoupling and dramatic swelling.
  • Mitochondrial swelling occurs without depolarization or pore opening.
  • DFX increases inner mitochondrial membrane proton permeability.
  • Intracellular osmotic gradients prevent water movement into mitochondria.
  • Other iron chelators do not induce mitochondrial swelling.

Conclusions:

  • DFX causes organ toxicity via an off-target effect on the inner mitochondrial membrane.
  • This off-target effect disrupts mitochondrial volume regulation.
  • The mechanism of DFX toxicity is distinct from its iron-chelating activity.

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