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Molecular Mechanisms Responsible for Pharmacological Effects of Genipin on Mitochondrial Proteins.
Kreiter, Jürgen; Rupprecht, Anne; Zimmermann, Lars; Moschinger, Michael; Rokitskaya, Tatyana I; Antonenko, Yuri N; Gille, Lars; Fedorova, Maria; Pohl, Elena E.
Affiliation
  • Kreiter J; Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
  • Rupprecht A; Rostock University Medical Center, Rostock, Mecklenburg-Vorpommern, Germany.
  • Zimmermann L; Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
  • Moschinger M; Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
  • Rokitskaya TI; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Antonenko YN; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Gille L; Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
  • Fedorova M; Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Center for Biotechnology and Biomedicine, University of Leipzig, Leipzig, Germany.
  • Pohl EE; Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria. Electronic address: elena.pohl@vetmeduni.ac.at.
Biophys J ; 117(10): 1845-1857, 2019 11 19.
Article in En | MEDLINE | ID: mdl-31706565
Genipin, a natural compound from Gardenia jasminoides, is a well-known compound in Chinese medicine that is used for the treatment of cancer, inflammation, and diabetes. The use of genipin in classical medicine is hindered because of its unknown molecular mechanisms of action apart from its strong cross-linking ability. Genipin is increasingly applied as a specific inhibitor of proton transport mediated by mitochondrial uncoupling protein 2 (UCP2). However, its specificity for UCP2 is questionable, and the underlying mechanism behind its action is unknown. Here, we investigated the effect of genipin in different systems, including neuroblastoma cells, isolated mitochondria, isolated mitochondrial proteins, and planar lipid bilayer membranes reconstituted with recombinant proteins. We revealed that genipin activated dicarboxylate carrier and decreased the activity of UCP1, UCP3, and complex III of the respiratory chain alongside with UCP2 inhibition. Based on competitive inhibition experiments, the use of amino acid blockers, and site-directed mutagenesis of UCP1, we propose a mechanism of genipin's action on UCPs. At low concentrations, genipin binds to arginine residues located in the UCP funnel, which leads to a decrease in UCP's proton transporting function in the presence of long chain fatty acids. At concentrations above 200 µM, the inhibitory action of genipin on UCPs is overlaid by increased nonspecific membrane conductance due to the formation of protein-genipin aggregates. Understanding the concentration-dependent mechanism of genipin action in cells will allow its targeted application as a drug in the above-mentioned diseases.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Mitochondrial Proteins / Iridoids Limits: Animals / Humans Language: En Journal: Biophys J Year: 2019 Document type: Article Affiliation country: Austria Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Mitochondrial Proteins / Iridoids Limits: Animals / Humans Language: En Journal: Biophys J Year: 2019 Document type: Article Affiliation country: Austria Country of publication: United States