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


ABSTRACT: 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.

SUBMITTER: Gottwald EM 

PROVIDER: S-EPMC6994599 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Gottwald Esther M EM   Schuh Claus D CD   Drücker Patrick P   Haenni Dominik D   Pearson Adam A   Ghazi Susan S   Bugarski Milica M   Polesel Marcello M   Duss Michael M   Landau Ehud M EM   Kaech Andres A   Ziegler Urs U   Lundby Anne K M AKM   Lundby Carsten C   Dittrich Petra S PS   Hall Andrew M AM  

Scientific reports 20200131 1


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 expla  ...[more]

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