National Institute for Research of Metabolic and Cardiovascular Diseases
Published January 1, 2024 | Version v1
Journal article Open

Chelation of mitochondrial iron as an antiparasitic strategy

Authors/Creators

  • 1. Department of Parasitology, Faculty ofScience, Charles University, Vestec 25250, Czech Republic
  • 2. Institut klinicke a experimentalni mediciny
  • 3. nstitute of Biotechnology, CzechAcademy of Sciences, Vestec 25250, Czech Republic;Department of Organic Chemistry, Faculty of Science, CharlesUniversity, Prague 128 00, Czech Republic
  • 4. Graduate Program in Areas of Basic andApplied Biology, Instituto de Ciê ncias Biomédicas AbelSalazar, Universidade do Porto, Porto 4050-313, Portugal;Centre for Infectious Diseases, Parasitology, HeidelbergUniversity Hospital, Heidelberg 69120, Germany
  • 5. Centre for Infectious Diseases, Parasitology,Heidelberg University Hospital, Heidelberg 69120, Germany
  • 6. Institute of Parasitology, Biology Centre,Academy of Sciences of the Czech Republic, České Budě jovice37005, Czech Republic
  • 7. Institute of Biotechnology, Czech Academy ofSciences, Vestec 25250, Czech Republic
  • 8. Department of Parasitology, Faculty of Science,Charles University, Vestec 25250, Czech Republic

Description

Iron, as an essential micronutrient, plays a crucial role in host-pathogen interactions. In order to limit the growth of the pathogen, a common strategy of innate immunity includes withdrawing available iron to interfere with the cellular processes of the microorganism. Against that, unicellular parasites have developed powerful strategies to scavenge iron, despite the effort of the host. Iron-sequestering compounds, such as the approved and potent chelator deferoxamine (DFO), are considered a viable option for therapeutic intervention. Since iron is heavily utilized in the mitochondrion, targeting iron chelators in this organelle could constitute an effective therapeutic strategy. This work presents mitochondrially targeted DFO, mitoDFO, as a candidate against a range of unicellular parasites with promising in vitro efficiency. Intracellular Leishmania infection can be cleared by this compound, and experimentation with Trypanosoma brucei 427 elucidates its possible mode of action. The compound not only affects iron homeostasis but also alters the physiochemical properties of the inner mitochondrial membrane, resulting in a loss of function. Furthermore, investigating the virulence factors of pathogenic yeasts confirms that mitoDFO is a viable candidate for therapeutic intervention against a wide spectrum of microbe-associated diseases.

Notes

We acknowledge CF Biophysic of CIISB, Instruct-CZ Centre,supported by MEYS CR (LM2023042), and European RegionalDevelopment Fund-Project “UP CIISB” (No. CZ.02.1.01/0.0/0.0/18_046/0015974), CePaViP provided by ERDF and MEYSCR (reg. no. CZ.02.1.01/0.0/0.0/16_019/0000759), and theGrant Agency of Charles University (406722). L.W. and J.S.were supported in part by Research Programme no. 18:Preclinical evaluation of potential drugs�Strategy AV21 ofthe Czech Academy of Sciences and Programme EXCELES, no.LX22NPO5104, European Union�Next Generation EU. M.M.was supported by the Fundação para a Ciência e a Tecnologia(PD/BD/128002/2016), and M.G. was supported by theBaden-Wü rttemberg Foundation (Grant number 1.16101.17) and the German Research Foundation�project number240245660�SFB 1129. D.S. was supported by the CzechScience Foundation (GA CR) project no. 21-11299S. V.L. wassupported by the MEMOVA project, EU OperationalProgramme Research, Development and Education no.CZ.02.2.69/0.0/0.0/18_053/0016982. The authors acknowl-edge the support from the European Cooperation in Science andTechnology (COST) Action CA21115.

Files

arbon-et-al-2024-chelation-of-mitochondrial-iron-as-an-antiparasitic-strategy.pdf

Files (6.0 MB)

Additional details

Related works

Has metadata
38287902 (PMID)
Is part of
2373-8227 (ISSN)
References
10.1021/acsinfecdis.3c00529 (DOI)