Abstract: FR-PO148

The Iron Chelator Deferasirox Causes Kidney Disease via Mitochondrial Dysfunction

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 001 AKI: Basic


  • Gottwald, Esther M, University of Zurich, Zurich, Switzerland
  • Schuh, Claus Dieter, University of Zurich, Zurich, Switzerland
  • Haenni, Dominik, University of Zurich, Zurich, Switzerland
  • Ghazi, Susan, University of Zurich, Zurich, Switzerland
  • Bugarski, Milica, University of Zurich, Zurich, Switzerland
  • Duss, Michael, University of Zurich, Zurich, Switzerland
  • Landau, Ehud M, University of Zurich, Zurich, Switzerland
  • Hall, Andrew, University of Zurich, Zurich, Switzerland

Deferasirox (DFX) is an oral iron chelator widely used in individuals at high risk of iron overload. It frequently causes kidney disease, by previously unknown mechanisms. Toxicity is localized to the proximal tubule (PT) and manifests clinically as the renal Fanconi syndrome (FS). PT cells are densely packed with mitochondria, which require iron for normal metabolism. We hypothesized that DFX causes kidney disease via mitochondrial toxicity.


Experimental models: PT-derived cell line, ex vivo mouse kidney cortex, in vivo mouse kidney. Techniques: confocal/multiphoton live imaging, electron microscopy, oxygen consumption measurements.


In PT-derived cells and fresh slices of mouse kidney cortex we discovered that DFX induces rapid swelling of mitochondria, leading ultimately to rupture of the inner mitochondrial membrane (IMM). Other iron chelators did not have the same effect. Mitochondria remained polarized during the swelling process, which was not prevented by inhibition of the permeability transition pore, but was rapidly reversed by the addition of iron. Of note, DFX did not inhibit oxygen consumption or cause oxidative stress, and targeted anti-oxidants did not prevent the phenotype. Interestingly, DFX-induced mitochondrial swelling and rupture was accelerated by stimulation of respiratory chain (RC) activity, whilst RC inhibition had the opposite effect, suggesting that swelling is an active process. Moreover, DFX did not induce rupture in an artificial lipid vesicle model of the IMM, implying that toxicity requires proteins normally expressed within mitochondria.
Using EM and intravital multiphoton microscopy, we observed that mice given DFX for 10 days showed evidence of mitochondrial swelling and dysfunction in vivo, exclusively in the PT, as well as impaired solute transport (consistent with FS). DFX is mainly albumin bound in blood, and we found that albumin binding reduced its toxicity in vitro, which might explain why the drug is tolerated by patients. Furthermore, since albumin is actively taken up by the PT, this could also explain the localization of DFX toxicity to this nephron segment.


In summary, we have found that DFX induces swelling and rupture of mitochondria in the PT, which most likely explains why it causes kidney disease in humans


  • Government Support - Non-U.S.