title: Mitochondrial Probe Methyltriphenylphosphonium (TPMP) Inhibits the Krebs Cycle Enzyme 2-Oxoglutarate Dehydrogenase.
abstract: Methyltriphenylphosphonium (TPMP) salts have been widely used to measure the mitochondrial membrane potential and the triphenylphosphonium (TPP+) moiety has been attached to many bioactive compounds including antioxidants to target them into mitochondria thanks to their high affinity to accumulate in the mitochondrial matrix. The adverse effects of these compounds on cellular metabolism have been insufficiently studied and are still poorly understood. Micromolar concentrations of TPMP cause a progressive inhibition of cellular respiration in adherent cells without a marked effect on mitochondrial coupling. In permeabilized cells the inhibition was limited to NADH-linked respiration. We found a mixed inhibition of the Krebs cycle enzyme 2-oxoglutarate dehydrogenase complex (OGDHC) with an estimated IC50 3.93 [3.70-4.17] mM, which is pharmacologically plausible since it corresponds to micromolar extracellular concentrations. Increasing the lipophilic character of the used TPP+ compound further potentiates the inhibition of OGDHC activity. This effect of TPMP on the Krebs cycle ought to be taken into account when interpreting observations on cells and mitochondria in the presence of TPP+ derivatives. Compounds based on or similar to TPP+ derivatives may also be used to alter OGDHC activity for experimental or therapeutic purposes.
authors.affiliation: Laboratory for Metabolism and Bioenergetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic.|Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Moustafa
authors.initials: M
authors.lastname: Elkalaf
authors.affiliation: Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.|Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Tůma
authors.affiliation: Department of Sport Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic.|Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Weiszenstein
authors.affiliation: Department of Sport Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic.|Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Polák
authors.affiliation: Laboratory for Metabolism and Bioenergetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic.|Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.|Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0002-1786-7562
authors.initials: J
authors.lastname: Trnka
mesh_terms: D000818:Animals; D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000187:drug effects / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects*; D005969:Glutamate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000201:enzymology; D009861:Onium Compounds / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014320:Triphenylmethyl Compounds / Q000494:pharmacology*
chemical_list: D009861:Onium Compounds; D011768:Pyruvate Dehydrogenase Complex; D014320:Triphenylmethyl Compounds; C011561:triphenylmethylphosphonium; D008291:Malate Dehydrogenase; D007521:Isocitrate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex; D005969:Glutamate Dehydrogenase; D002950:Citrate (si)-Synthase