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

• Published in: Scientific reports Vol. 10; no. 1; p. 1577
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.01.2020; Nature Publishing Group
• Subjects: 14; 631/443/272; 692/4022; Animals; Cell Line; Chelating agents; Deferasirox - pharmacology; Depolarization; Humanities and Social Sciences; Humans; Iron; Iron Chelating Agents - pharmacology; Kidney - drug effects; Kidney - metabolism; Male; Membrane permeability; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Microscopy, Electron; Mitochondria - drug effects; Mitochondria - ultrastructure; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Mitochondrial permeability transition pore; multidisciplinary; Permeability; Permeability - drug effects; Protons; Science; Science (multidisciplinary); Toxicity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-58386-9

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.