Springe zum Hauptinhalt Springe zur Navigation
Veterinärmedizinische Universität Wien

Mitochondria and mitochondrial Reactive Oxygen Species (ROS)

Lars Gille, Katrin Staniek

Overview

Endoperoxides may have potential as antiprotozoal drug in vitro and in vivo

Our research topics are the role of mitochondria and mitochondrial ROS as drug targets and in toxicological mechanisms. Recent research activities focused on the one hand on the involvement of mitochondria as drug targets in protozoal1 and cancer cells2. On the other hand our latest research activities have shown that endoperoxides can be useful antileishmanial drugs in vitro and in vivo3. A current project is elucidating the mechanism why these endoperoxides are more toxic to protozoal parasites than to mammalian host cells, such as macrophages.

As a part of these research activities we study the conditions under which xenobiotics trigger ROS formation and inhibition of mitochondrial electron transfer in mammalian and leishmanial mitochondria, since these are essential elements of the intrinsic pathway of apoptosis. Our research activities revealed that mitochondria are often involved in the action of antiprotozoal and anticancer drugs, however, not always being a direct pharmacological target4. Current results on endoperoxides demonstrate that this compound group may have potential as antiprotozoal drug.

Electron Spin Resonance spectroscopy (ESR)

Principle of ESR spectroscopy

A major methodical focus of our research in cooperation with several other research groups is the Electron Spin Resonance (ESR) spectroscopy. This is a method to study (bio-) molecules, which have one or more unpaired electrons, such as free radicals (including ROS and RNS) and complexes of transition metals. Besides the importance of this technique for non-biological subjects, in the last decades several radical species were detected in living organisms, such as oxygen radicals or the endothelium-derived relaxing factor (EDRF, NO), which are of significant biological importance.

Furthermore, this technique is relevant in biophysical research for elucidation of lipid membrane properties of cells and organelles as well as the binding of labeled molecules, such as drugs, to cellular structures. For the application of ESR spectroscopy in biological systems several specialized techniques were developed.

The ESR spectroscopy was already employed in our lab for following applications:

  • Detection of oxygen radicals in cell culture models5,6
  • Detection of vitamin c radicals, transferrin, ceruloplasmin and NO (EDRF) in blood and plasma7
  • Characterization of mitochondrial electron carriers8,9
  • Measurement of membrane fluidity of lipid membranes10
  • Elucidation of cytostatic transition metal complexes11

Other possible applications are the detection of irradiated food, aging of beer, monitoring of mineral oil degradation, antioxidant properties of food, monitoring of asbestos redox activity and many other fields.

References

1. L. Monzote, M. Garcia, J. Pastor, L. Gil, R. Scull, L. Maes, P. Cos, and L. Gille.
Essential oil from Chenopodium ambrosioides and main components: Activity against Leishmania, their mitochondria and other microorganisms. Exp.Parasitol. 136:20-26, 2014.

2. J. Gruber, K. Staniek, C. Krewenka, R. Moldzio, A. Patel, S. Bohmdorfer, T. Rosenau, and L. Gille.
Tocopheramine succinate and tocopheryl succinate: mechanism of mitochondrial inhibition and superoxide radical production. Bioorg.Med.Chem. 22 (2):684-691, 2014.

3. J. Pastor, M. Garcia, S. Steinbauer, W. N. Setzer, R. Scull, L. Gille, and L. Monzote.
Combinations of ascaridole, carvacrol, and caryophyllene oxide against Leishmania. Acta Tropica 145:31-38, 2015.

4. L. M. Fidalgo and L. Gille.
Mitochondria and trypanosomatids: targets and drugs. Pharm.Res. 28 (11):2758-2770, 2011.

5. A. Haschemi, P. Kosma, L. Gille, C. R. Evans, C. F. Burant, P. Starkl, B. Knapp, R. Haas, J. A. Schmid, C. Jandl, S. Amir, G. Lubec, J. Park, H. Esterbauer, M. Bilban, L. Brizuela, J. A. Pospisilik, L. E. Otterbein, and O. Wagner.
The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 15 (6):813-826, 2012.

6. W. Warsch, E. Grundschober, A. Berger, L. Gille, S. Cerny-Reiterer, A. S. Tigan, A. Hoelbl-Kovacic, P. Valent, R. Moriggl, and V. Sexl.
STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia. Oncotarget 3 (12):1669-1687, 2012.

7. L. Gille, M. Kleiter, M. Willmann, and H. Nohl.
Paramagnetic species in the plasma of dogs with lymphoma prior to and after treatment with doxorubicin. An ESR study. Biochem.Pharmacol. 64 (12):1737-1744, 2002.

8. H. Nohl, L. Gille, and A. V. Kozlov.
Antioxidant-derived prooxidant formation from ubiquinol. Free Radic.Biol.Med. 25 (6):666-675, 1998.

9. A. Müllebner, A. Patel, W. Stamberg, K. Staniek, T. Rosenau, T. Netscher, and L. Gille.
Modulation of the mitochondrial cytochrome bc1 complex activity by chromanols and related compounds. Chem.Res.Toxicol. 23 (1):193-202, 2010.

10. E. A. Malingriaux, A. Ruprecht, L. Gille, O. Jovanovic, P. Jezek, M. Jaburek, and E. E. Pohl.
Fatty acids are key in 4-hydroxy-2-nonenal-mediated activation of uncoupling proteins 1 and 2. Plos One 8 (10):e77786, 2013.

11. C. R. Kowol, P. Heffeter, W. Miklos, L. Gille, R. Trondl, L. Cappellacci, W. Berger, and B. K. Keppler.
Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds. J.Biol.Inorg.Chem. 17 (3):409-423, 2012.

Zum Seitenanfang