Book of Abstracts - Ruhr-Universität Bochum

P-72
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Analyzing Drug Action on Mitochondrial Targets using Functional Assays with
Isolated Biological Active Mitochondria
Suzan Can, a Ana Kitanovic, a Igor Kitanovic, a Annegret Hille, b Ronald Gust, b Melanie Oleszak, c
Yvonne Geldmacher, c William S. Sheldrick, c Andreas Meyer, d Riccardo Rubbiani, d Ingo Ott d and
Stefan Wölfl *a
a Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Im Neuenheimer Feld
364, 69120 Heidelberg, Germany. b Institute of Pharmacy, Department of Pharmaceutical Chemistry,
Free university of Berlin, Germany. c Faculty of Chemistry and Biochemistry, Department of
Analytical Chemistry, University Bochum. d Institute of Pharmaceutical Chemistry, Technische
Universität Braunschweig, Germany. email: wolfl@uni-hd.de
Mitochondria play crucial roles in living cells. They are not only the source of energy via oxidative
phosphorylation and ATP synthesis, but are also an important regulators of cellular survival and in the
control of programmed cell death. Mitochondrial damage and inhibition of the electron transfer in the
respiratory chain can trigger the production of reactive oxygen species (ROS) and the release of
cytochrome c. The latter initiates mitochondrial induction of apoptosis. Previous studies in intact cells
showed that several bioorganometallic compounds significantly induced ROS formation and triggered
cell death inducing pro-apoptotic pathways.
To further elucidate their specific activity we wanted to investigate if mitochondria and mitochondrial
activity are direct targets of some of these compounds. With the central role of mitochondria in the
regulation of cell death such compounds could play an important role for anti-cancer therapy to trigger
cell death in proliferating cancer cells.
We isolated mitochondria from mouse liver and established a series of tests that show mitochondrial
functionality. With these functional assays for several complexes of the respiratory chain and by
measuring oxygen consumption we analysed the capability of various substances to influence
respiration and selectively inhibit respiratory chain components in isolated mitochondria. Results
revealed that some salophene iron complexes (AG Gust) and rhodium (III) polypyridyl complexes
(AG Sheldrick) directly inhibit mitochondrial respiration. Furthermore it could be shown that
treatment with several bioorganometallic substances lead to a release of cytochrome c and to changes
of mitochondrial membrane potential which indicates a strong influence on the integrity of the
mitochondrial membrane.
This work is supported by the DFG as part of the Forschergruppe FOR630.
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