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

Gottwald, Esther M; Schuh, Claus D; Drücker, Patrick; Haenni, Dominik; Pearson, Adam; Ghazi, Susan; Bugarski, Milica; Polesel, Marcello; Duss, Michael; Landau, Ehud M; Kaech, Andres; Ziegler, Urs; Lundby, Anne K M; Lundby, Carsten; Dittrich, Petra S; Hall, Andrew M

doi:10.1038/s41598-020-58386-9

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Gottwald, E. M., Schuh, C. D., Drücker, P., Haenni, D., Pearson, A., Ghazi, S., Bugarski, M., Polesel, M., Duss, M., Landau, E. M., Kaech, A., Ziegler, U., Lundby, A. K. M., Lundby, C., Dittrich, P. S., & Hall, A. M. (2020). The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on inner membrane permeability. Scientific Reports, 10(1), 1577. https://doi.org/10.1038/s41598-020-58386-9

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 mitochondri