The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on inner membrane permeability.
- Gottwald EM Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Schuh CD Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Drücker P Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland.
- Haenni D Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Pearson A Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Ghazi S Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Bugarski M Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Polesel M Institute of Anatomy, University of Zurich, Zurich, Switzerland.
- Duss M Department of Chemistry, University of Zurich, Zurich, Switzerland.
- Landau EM Department of Chemistry, University of Zurich, Zurich, Switzerland.
- Kaech A Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland.
- Ziegler U Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland.
- Lundby AKM Institute of Physiology, University of Zurich, Zurich, Switzerland.
- Lundby C Institute of Physiology, University of Zurich, Zurich, Switzerland.
- Dittrich PS Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland.
- Hall AM Institute of Anatomy, University of Zurich, Zurich, Switzerland. andrew.hall@uzh.ch.
- 2020-02-02
Published in:
- Scientific reports. - 2020
Animals
Cell Line
Deferasirox
Humans
Iron Chelating Agents
Kidney
Male
Membrane Potential, Mitochondrial
Mice
Mice, Inbred C57BL
Microscopy, Electron
Mitochondria
Mitochondrial Membranes
Permeability
English
The iron chelator Deferasirox (DFX) causes severe toxicity in patients for reasons that were previously unexplained. Here, using the kidney as a clinically relevant in vivo model for toxicity together with a broad range of experimental techniques, including live cell imaging and in vitro biophysical models, we show that DFX causes partial uncoupling and dramatic swelling of mitochondria, but without depolarization or opening of the mitochondrial permeability transition pore. This effect is explained by an increase in inner mitochondrial membrane (IMM) permeability to protons, but not small molecules. The movement of water into mitochondria is prevented by altering intracellular osmotic gradients. Other clinically used iron chelators do not produce mitochondrial swelling. Thus, DFX causes organ toxicity due to an off-target effect on the IMM, which has major adverse consequences for mitochondrial volume regulation.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1038/s41598-020-58386-9
- PMID 32005861
- Persistent URL
- https://sonar.ch/global/documents/136502
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