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27. Effect of the Catechol-O-Methyltransferase Inhibitors Tolcapone and Entacapone on Fatty Acid Metabolism in HepaRG Cells

Author

Grünig, David, Felser, Andrea, Duthaler, Urs, Bouitbir, Jamal, and Krähenbühl, Stephan

Abstract

Tolcapone and entacapone are catechol-O-methyltransferase inhibitors used in patients with Parkinson's disease. For tolcapone, patients with liver failure have been reported with microvesicular steatosis observed in the liver biopsy of 1 patient. We therefore investigated the impact of tolcapone and entacapone on fatty acid metabolism in HepaRG cells exposed for 24 h and on acutely exposed mouse liver mitochondria. In HepaRG cells, tolcapone induced lipid accumulation starting at 100 µM, whereas entacapone was ineffective up to 200 µM. In HepaRG cells, tolcapone-inhibited palmitate metabolism and activation starting at 100 µM, whereas entacapone did not affect palmitate metabolism. In isolated mouse liver mitochondria, tolcapone inhibited palmitate metabolism starting at 5 µM and entacapone at 50 µM. Inhibition of palmitate activation could be confirmed by the acylcarnitine pattern in the supernatant of HepaRG cell cultures. Tolcapone-reduced mRNA and protein expression of long-chain acyl-CoA synthetase 1 (ACSL1) and protein expression of ACSL5, whereas entacapone did not affect ACSL expression. Tolcapone increased mRNA expression of the fatty acid transporter CD36/FAT, impaired the secretion of ApoB100 by HepaRG cells and reduced the mRNA expression of ApoB100, but did not relevantly affect markers of fatty acid binding, lipid droplet formation and microsomal lipid transfer. In conclusion, tolcapone impaired hepatocellular fatty acid metabolism at lower concentrations than entacapone. Tolcapone increased mRNA expression of fatty acid transporters, inhibited activation of long-chain fatty acids and impaired very low-density lipoprotein secretion, causing hepatocellular triglyceride accumulation. The findings may be relevant in patients with a high tolcapone exposure and preexisting mitochondrial dysfunction.

Published
2021

28. Hepatocellular Toxicity of Imidazole and Triazole Antimycotic Agents

Author

Haegler, Patrizia, Joerin, Lorenz, Krähenbühl, Stephan, and Bouitbir, Jamal

Abstract

Hepatotoxicity has been described for all antimycotic azoles currently marketed. A possible mechanism involving mitochondrial dysfunction has been postulated for ketoconazole, but not for the other azoles. The aim of the current investigations was to study the toxicity of different azoles in human cell models and to find out mechanisms of their toxicity. In HepG2 cells, posaconazole and ketoconazole were cytotoxic starting at 20 and 50 µM and decreased the cellular ATP content starting at 5 and 10 µM, respectively. In HepaRG cells, cytotoxicity started at 20 and 100 µM for posaconazole and ketoconazole, respectively, and was slightly accentuated by cytochrome P450 3A4 induction with rifampicin and 1A2 with 3-methylcholantrene. Voriconazole and fluconazole were not cytotoxic. In isolated mouse liver mitochondria, ketoconazole impaired membrane potential and complex I activity, whereas the other azoles were not toxic. In HepG2 cells exposed for 24 h, both posaconazole and ketoconazole (but not fluconazole or voriconazole) decreased the mitochondrial membrane potential, impaired the function of enzyme complexes of the electron transport chain, were associated with mitochondrial superoxide accumulation, decreased mitochondrial DNA and induced apoptosis. In HepG2 cells with mitochondrial dysfunction induced by the vitamin B12 antagonist hydroxy-cobalamin[c-lactam], cytotoxicity and/or ATP depletion was more accentuated than in untreated cells. We conclude that ketoconazole and posaconazole are mitochondrial toxicants starting at concentrations, which can be reached in vivo. Cytotoxicity and ATP depletion are more accentuated in cells with mitochondrial damage, suggesting that preexisting mitochondrial dysfunction is a susceptibility factor for hepatotoxicity associated with these drugs.

Published
2021

30. Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity.

Author

Pearson, Adam, Haenni, Dominik, Bouitbir, Jamal, Hunt, Matthew, Payne, Brendan A I, Sachdeva, Ashwin, Hung, Rachel K Y, Post, Frank A, Connolly, John, Nlandu-Khodo, Stellor, Jankovic, Nevena, Bugarski, Milica, and Hall, Andrew M

Subjects
TENOFOVIR, OXYGEN consumption, ADENOSINE triphosphatase, MITOCHONDRIA, DNA fingerprinting, RENAL biopsy, METABOLOMICS
Abstract

Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling—including oxygen consumption measurements, metabolomics, and transcriptomics—we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity. Graphical Abstract [ABSTRACT FROM AUTHOR]

Published
2023
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32. Mitochondrial physiology: Gnaiger Erich et al ― MitoEAGLE Task Group

Author

Gnaiger, Erich, Aasander Frostner, Eleonor, Abdul Karim, Norwahidah, Abdel-Rahman, Engy Ali, Abumrad, Nada A, Acuna-Castroviejo, Dario, Adiele, Reginald C, Ahn, Bumsoo, Alencar, MB, Ali, Sameh S, Almeida, Angeles, Alton, Lesley, Alves, Marco G, Amati, Francesca, Amoedo, Nivea Dias, Amorim, Ricardo, Anderson, Ethan J, Andreadou, Ioanna, Antunes, Diana, Arago, Marc, Aral, Cenk, Arandarcikaite, Odeta, Arias-Reyes, Christian, Armand, Anne-Sophie, Arnould, Thierry, Avram, Vlad Florian, Axelrod, Christopher L, Bairam, Aida, Bailey, Damian M, Bajpeyi, Sudip, Bajzikova, Martina, Bakker, Barbara M, Barlow, Jonathan, Bardal, Tora, Banni, A, Bastos Sant'Anna Silva, Ana Carolina, Batterson, Philip, Battino, Maurizio, Bazil, Jason, Beard, Daniel A, Beleza, Jorge, Bednarczyk, Piotr, Bello, Fiona, Ben-Shachar, Dorit, Bento Guida, Jose Freitas, Bergdahl, Andreas, Berge, Rolf K, Bergmeister, Lisa, Bernardi, Paolo, Berridge, Michael V, Bettinazzi, Stefano, Bishop, David, Blier, Pierre U, Blindheim, Dan Filip, Boardman, Neoma T, Boetker, Hans Erik, Borchard, Sabine, Boros, Mihaly, Borsheim, Elisabet, Borras, Consuelo, Borutaite, Vilma, Botella, Javier, Bouillaud, Frederic, Bouitbir, Jamal, Boushel, Robert C, Bovard, Josh, Bravo-Sagua, Roberto, Breton, Sophie, Brown, David A, Brown, Guy C, Brown, Robert A, Brozinick, Joseph T, Buettner, Garry R, Burtscher, Johannes, Bustos, Matilde, Calabria, Elisa, Calbet, Jose A, Calzia, Enrico, Cannon, Daniel T, Cano Sanchez, Maria, Canto Alvarez, Carles, Cardinale, D, Cardoso, Luiza Helena Daltro, Carvalho, Eugenia, Casado Pinna, Marta, Cassar, Samantha, Castelo, Maria P, Castilho, Roger F, Cavalcanti-de-Albuquerque, Joao Paulo, Cecatto, Cristiane, Celen, Murat C, Cervinkova, Zuzana, Chabi, Beatrice, Chakrabarti, Lisa, Chakrabarti, Sasanka, Chaurasia, Bhagirath, Chen, Quan, Chicco, Adam J, Chinopoulos, Christos, Chowdhury, Subir K, Cizmarova, Beata, Clementi, Emilio, Coen, Paul M, Cohen, Bruce H, Coker, Robert H, Collin-Chenot, Anne, Coughlan, Melinda T, Coxito, Petro, Crisostomo, Luis, Crispim, Marcell, Crossland, Hannah, Dahdah, Norma, Dalgaard, Louise T, Dambrova, Maija, Danhelovska, Tereza, Darveau, Charles A, Darwin, Paula M, Das, Anibh M, Dash, Ranjan K, Davidova, Eliska, Davis, Michael S, Dayanidhi, Sudarshan, De Bem, Andreza Fabro, De Goede, Paul, De Palma, Clara, De Pinto, Vito, Dela, F, Dembinska-Kiec, Aldona, Detraux, Damien, Devaux, Yvan, Di Marcello, Marco, Di Paola, Floriana Jessica, Dias, Candida, Dias, Tania R, Diederich, Marc, Distefano, Giovanna, Djafarzadeh, Siamak, Doermann, Niklas, Doerrier, Carolina, Dong, Lan-Feng, Donnelly, Chris, Drahota, Zdenek, Duarte, Filipe Valente, Dubouchaud, Herve, Duchen, Michael R, Dumas, Jean-Francois, Durham, William J, Dymkowska, Dorota, Dyrstad, Sissel E, Dyson, Alex, Dzialowski, Edward M, Eaton, Simon, Ehinger, Johannes, Elmer, Eskil, Endlicher, Rene, Engin, Ayse B, Escames, Germaine, Evinova, Andrea, Ezrova, Zuzana, Falk, Marni Joy, Fell, David A, Ferdinandy, Peter, Ferko, Miroslav, Fernandez-Ortiz, Marisol, Erika, Fernandez-Vizarra, Ferreira, Julio Cesar Batista, Ferreira, Rita, Ferri, Alessandra, Festuccia, WT, Fessel, Joshua P, Filipovska, Aleksandra, Fisar, Zdenek, Fischer, Christine, Fischer, Michael, Fisher, Gordon, Fisher, Joshua J, Fontanesi, Flavia, Forbes-Hernandez, Tamara Y, Ford, Ellen, Fornaro, Mara, Fuertes Agudo, Marina, Fulton, Montana, Galina, Antonio, Galkin, Alexander, Gallee, Leon, Galli, Gina L, Gama Perez, Pau, Gan, Zhenji, Ganetzky, Rebecca, Gao, Yun, Garcia, Geovana S, Garcia-Rivas, Gerardo, Garcia-Roves, Pablo Miguel, Garcia-Souza, Luiz Felipe, Garlid, Keith D, Garrabou, Gloria, Garten, Antje, Gastaldelli, Amalia, Gayen, Jiaur, Genders, Amanda J, Genova, Maria Luisa, Giampieri, Francesca, Glatz, Jan FC, Giovarelli, Matteo, Goikoetxea Usandizaga, Naroa, Goncalo Teixeira da Silva, Rui, Goncalves, Debora Farina, Gonzalez-Armenta, Jenny L, Gonzalez-Francesqua, A, Gonzalez-Freire, Marta, Gonzalo, Hugo, Goodpaster, Bret H, Gorr, Thomas A, Gourlay, Campbell W, Grams, Bente, Granata, Cesare, Grefte, Sander, Grilo, Luis, Guarch, Meritxell Espino, Gueguen, Naig, Gumeni, Sentiljana, Haas, Clarissa B, Haavik, Jan, Hachmo, Yafit, Haendeler, Judith, Haider, Markus, Hajrulahovic, Anesa, Hamann, Andrea, Han, Jin, Han, Woo Hyun, Hancock, Chad R, Hand, Steven C, Handl, Jiri, Hansikova, Hana, Hardee, Justin P, Hargreaves, Ian P, Harper, Mary Ellen, Harrison, David K, Hassan, Hazirah, Hatakova, Zuzana, Hausenloy, Derek J, Heales, Simon JR, Heiestad, Christina, Hellgren, Kim T, Henrique, Alexandrino, Hepple, Russell T, Hernansanz-Agustin, Pablo, Hewakapuge, Sudinna, Hickey, Anthony J, Ho, Dieu Hien, Hoehn, Kyle L, Hoel, Frederik, Holland, Olivia J, Holloway, Graham P, Holzner, Lorenz, Hoppel, Charles L, Hoppeler, H, Hoppel, Florian, Houstek, Josef, Huete-Ortega, Maria, Hyrossova, Petra, Iglesias-Gonzalez, Javier, Indiveri, Cesare, Irving, Brian A, Isola, Raffaella, Iyer, Shilpa, Jackson, Christophe B, Jadiya, Pooja, Jana, Prado Fabian, Jandeleit-Dahm, K, Jang, David H, Jang, Young C, Janowska, Joanna, Jansen, Kirsten, Jansen-Duerr, Pidder, Jansone, Baiba, Jarmuszkiewicz, Wieslawa, Jaskiewicz, Anna, Jaspers, Richard T, Jedlicka, Jan, Jerome, Estaquier, Jespersen, Nichlas R, Jha, Rajan K, Joseph, Vincent, Juhasz, Laszlo, Jurczak, Michael J, Jurk, Diana, Kaambre, Tuuli, Kaczor, Jan J, Kainulainen, Heikki, Kampa, Rafal Pawel, Kandel, Sunil M, Kane, Daniel A, Kapferer, Werner, Kapnick, Senta, Kappler, Lisa, Karabatsiakis, Alexander, Karavaeva, Iuliia, Karkucinska-Wieckowska, Agnieszka, Kaur, Sarbjot, Keijer, Jaap, Keller, Markus A, Keppner, Gloria, Khamoui, Andy V, Kidere, Dita, Kilbaugh, Todd, Kim, Hyoung Kyu, Kim, Julian KS, Kimoloi, Sammy, Klepinin, Aleksandr, Klepinina, Lyudmila, Klingenspor, Martin, Klocker, Helmut, Komlódi, Timea, Kolasa, Iris, Koopman, Werner JH, Kopitar-Jerala, Natasa, Kowaltowski, Alicia J, Kozlov, Andrey V, Krajcova, Adela, Krako Jakovljevic, Nina, Kristal, Bruce S, Krycer, Jamer R, Kuang, Jujiao, Kucera, Otto, Kuka, Janis, Kwak, Hyo Bum, Kwast, Kurt, Kwon, Oh Sung, Laasmaa, Martin, Labieniec-Watala, Magdalena, Lai, Nicola, Lalic, Nebojsa M, Land, John M, Lane, Nick, Laner, Verena, Lanza, Ian R, Laouafa, Sofien, Larsen, Steen, Larsen, Terje S, Lavery, Gareth G, Lazou, Antigone, Ledo, Ana Margarida, Lee, Hong Kyu, Leeuwenburgh, Christiaan, Lehti, Maarit, Lemieux, Helene, Lenaz, Giorgio, Lerfall, Jorgen, Li, Pingan A, Li Puma, Lance, Liang, Liping, Liepins, Edgars, Lin, Chien-Te, Liu, Jiankang, Lopez, Luis C, Lucchinetti, Eliana, Ma, Tao, Macedo, Maria P, Machado, Ivo F, Maciej, Sarah, MacMillan-Crow, Lee Ann, Magalhaes, Jose, Magri, Andrea, Majtnerova, Pavlina, Makarova, Elina, Makrecka-Kuka, Marina, Malik, Afshan N, Marcouiller, Francois, Marechal, Amandine, Markova, Michaela, Markovic, Ivanka, Martin, Daniel S, Martins, Ana Dias, Martins, Joao D, Maseko, Tumisang Edward, Maull, Felicia, Mazat, Jean Pierre, McKenna, Helen T, McKenzie, Matthew, McMillan, Duncan GG, McStay, Gavin P, Menze, Michael A, Mendham, Amy, Mercer, John R, Merz, Tamara, Messina, Angela, Meszaros, Andras T, Methner, Axel, Michalak, Slawomir, Mila Guasch, Maria, Minuzzi, Luciele M, Misirkic Marjanovic, Maja, Moellering, Douglas R, Moisoi, Nicoleta, Molina, Anthony JA, Montaigne, David, Moore, Anthony L, Moore, Christy, Moreau, Kerrie, Moreira, Bruno P, Moreno-Sanchez, Rafael, Mracek, Tomas, Muccini, Anna Maria, Muntane, Jordi, Muntean, Danina M, Murray, Andrew J, Musiol, Eva, Nabben, Miranda, Nair, K Sreekumaran, Nehlin, Jan O, Nemec, Michal, Nesci, Salvatore, Neufer, P Darrell, Neuzil, Jiri, Neviere, Remi, Newsom, Sean A., Norman, Jennifer, Nozickova, Katerina, Nunes, Sara, Nuoffer, Jean-Marc, O'Brien, Kristin, O'Brien, Katie A, O'Gorman, Donal, Olgar, Yusuf, Oliveira, Ben, Oliveira, Jorge, Oliveira, Marcus F, Oliveira, Marcos Tulio, Oliveira, Pedro F, Oliveira, Paulo J, Olsen, Rolf Erik, Orynbayeva, Zulfiya, Osiewacz, Heinz D, Paez, Hector, Pak, Youngmi K, Pallotta, Maria L, Palmeira, Carlos M, Parajuli, Nirmala, Passos, Joao F, Passrugger, Manuela, Patel, Hemal H, Pavlova, Nadia, Pavlovic, Kasja, Pecina, Petr, Pedersen, Tina M, Perales, Jose Carlos, Pereira da Silva Grilo da Silva, Filomena, Pereira, Rita, Perez Valencia, Juan A, Perks, Kara L, Pesta, Dominik, Petit, Patrice X, Pettersen Nitschke, Ina Katrine, Pichaud, Nicolas, Pichler, Irene, Piel, Sarah, Pietka, Terri A, Pinho, Sonia A, Pino, Maria F, Pirkmajer, Sergej, Place, Nicolas, Plangger, Mario, Porter, Craig, Porter, Richard K, Preguica, Ines, Procaccio, Vincent, Prochownik, Edward V, Prola, Alexandre, Pulinilkunnil, Thomas, Puskarich, Michael A, Puurand, Marju, Radenkovic, Filip, Ramzan, Rabia, Rattan, Suresh IS, Reano, Simone, Reboredo, Patricia, Rees, Bernard B, Renner-Sattler, Kathrin, Rial, Eduardo, Robinson, Matthew M, Roden, Michael, Rodrigues, Ana Sofia, Rodriguez, Enrique, Rodriguez-Enriquez, Sara, Roesland, Gro Vatne, Rolo, Anabela Pinto, Ropelle, Eduardo R, Roshanravan, Baback, Rossignol, Rodrigue, Rossiter, Harry B, Rousar, Tomas, Rubelj, Ivica, Rybacka-Mossakowska, Joanna, Saada, Ann, Safaei, Zahra, Sarlak, Saharnaz, Salin, Karine, Salvadego, Desy, Sandi, Carmen, Saner, Nicholas, Santos, Diana, Sanz, Alberto, Sardao, Vilma, Sazanov, Leonid A, Scaife, Paula, Scatena, Roberto, Schartner, Melanie, Scheibye-Knudsen, Morten, Schilling, Jan M, Schlattner, Uwe, Schmitt, Sabine, Schneider Gasser, Edith Mariane, Schoenfeld, Peter, Schots, Pauke C, Schulz, Rainer, Schwarzer, Christoph, Scott, Graham R, Selman, Colin, Sendon, Pamella Marie, Shabalina, Irina G, Sharma, Pushpa, Sharma, Vipin, Shevchuk, Igor, Shirazi, Reza, Shiroma, Jonathan G, Siewiera, Karolina, Silber, Ariel M, Silva, Ana Maria, Sims, Carrie A, Singer, Dominique, Singh, Brijesh Kumar, Skolik, Robert A, Smenes, Benedikte Therese, Smith, James, Soares, Félix Alexandre Antunes, Sobotka, Ondrej, Sokolova, Inna, Solesio Torregrosa, M De la Encarnacion, Soliz, Jorge, Sonkar, Vijay K, Sova, Marina, Sowton, Alice P, Sparagna, Genevieve C, Sparks, Lauren M, Spinazzi, Marco, Stankova, Pavla, Starr, Jonathan, Stary, Creed, Stefan, Eduard, Stelfa, Gundega, Stepto, Nigel K, Stevanovic, Jelena, Stiban, Johnny, Stier, Antoine, Stocker, Roland, Storder, Julie, Sumbalova, Zuzana, Suomalainen, Wartiovaara Anu, Suravajhala, Prashanth, Svalbe, Baiba, Swerdlow, Russel H, Swiniuch, Daria, Szabo, Ildiko, Szewczyk, Adam, Szibor, Marten, Tanaka, Masashi, Tandler, Bernard, Tarnopolsky, Mark A, Tausan, Daniel, Tavernarakis, Nektarios, Tepp, Kersti, Teodoro, J, Thakkar, Himani, Thapa, Maheshwo, Thyfault, John P, Tomar, Dhanendra, Ton, Riccardo, Torp, May-Kristin, Torres-Quesada, Omar, Towheed, Atif, Treberg, Jason R, Tretter, Laszlo, Trewin, Adam J, Trifunovic, Aleksandra, Trivigno, Catherine, Tronstad, Karl Johan, Trougakos, Ioannis P, Truu, Laura, Tuncay, Erkan, Turan, Belma, Tyrrell, Daniel J, Urban, Tomas, Urner, Sofia, Valentine, Joseph Marco, Van Bergen, Nicole J, Van der Ende, Miranda, Varricchio, Frederick, Vaupel, Peter, Vella, Joanna, Vendelin, Marko, Verdaguer, IB, Vercesi, Anibal E, Vernerova, Andrea, Victor, Victor Manuel, Vieira Ligo Teixeira, Camila, Vidimce, Josif, Viel, Christian, Vieyra, Adalberto, Vilks, Karlis, Villena, Joseph A, Vincent, Vinnyfred, Vinogradov, Andrey D, Viscomi, Carlo, Vitorino, Rui Miguel Pinheiro, Vlachaki Walker, Julia, Vogt, Sebastian, Volani, Chiara, Volska, Kristine, Votion, Dominique-Marie, Vujacic-Mirski, Ksenija, Wagner, Brett A, Ward, Marie Louise, Warnsmann, Verena, Wasserman, David H, Watala, Cezary, Wei, Yau-Huei, Weinberger, Klaus M, White, Sarah, Whitfield, Jamie, Wickert, Anika, Wieckowski, Mariusz R, Wiesner, Rudolf J, Williams, Caroline M, Winwood-Smith, Hugh, Wohlgemuth, Stephanie E, Wohlwend, Martin, Wolff, Jonci Nikolai, Wrutniak-Cabello, Chantal, Wuest, Rob C I, Yokota, Takashi, Zablocki, Krzysztof, Zanon, Alessandra, Zanou, Nadege, Zaugg, Kathrin, Zaugg, Michael, Zdrazilova, Lucie, Zhang, Yong, Zhang, Yi Zhu, Zikova, Alena, Zischka, Hans, Zorzano, Antonio, Zujovic, Tijana, Zurmanova, Jitka, Zvejniece, Liga, Lagarrigue, Sylviane, Munro, Daniel, Pereira, Susana, Laranjinha, Joäo, Hecker, Matthias, Jusic, Amela, Prigione, Alessandro, Sommer, Natascha, Weissig, Volkmar, Guida, Bento, G, John G, Jones, JG, AMS - Tissue Function & Regeneration, AMS - Rehabilitation & Development, Physiology, Mito-Eagle - Evolution-Age-Gender-Lifestyle-Environment (Mito-Eagle), Oroboros Instruments, Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Gnaiger Erich, Aasander Frostner Eleonor, Abdul Karim Norwahidah, Abdel-Rahman Engy Ali, Abumrad Nada A, Acuna-Castroviejo Dario, Adiele Reginald C, Ahn Bumsoo, Alencar Mayke Bezerra, Ali Sameh S, Almeida Angeles, Alton Lesley, Alves Marco G, Amati Francesca, Amoedo Nivea Dias, Amorim Ricardo, Anderson Ethan J, Andreadou Ioanna, Antunes Diana, Arago Marc, Aral Cenk, Arandarcikaite Odeta, Arias-Reyes Christian, Armand Anne-Sophie, Arnould Thierry, Avram Vlad F, Axelrod Christopher L, Bailey Damian M, Bairam Aida, Bajpeyi Sudip, Bajzikova Martina, Bakker Barbara M, Banni Aml, Bardal Tora, Barlow J, Bastos Sant'Anna Silva Ana Carolina, Batterson Philip M, Battino Maurizio, Bazil Jason N, Beard Daniel A, Bednarczyk Piotr, Beleza Jorge, Bello Fiona, Ben-Shachar Dorit, Bento Guida Jose Freitas, Bergdahl Andreas, Berge Rolf K, Bergmeister Lisa, Bernardi Paolo, Berridge Michael V, Bettinazzi Stefano, Bishop David J, Blier Pierre U, Blindheim Dan Filip, Boardman Neoma T, Boetker Hans Erik, Borchard Sabine, Boros Mihaly, Boersheim Elisabet, Borras Consuelo, Borutaite Vilma, Botella Javier, Bouillaud Frederic, Bouitbir Jamal, Boushel Robert C, Bovard Josh, Bravo-Sagua Roberto, Breton Sophie, Brown David A, Brown Guy C, Brown Robert Andrew, Brozinick Joseph T, Buettner Garry R, Burtscher Johannes, Bustos Matilde, Calabria Elisa, Calbet Jose AL, Calzia Enrico, Cannon Daniel T, Cano Sanchez Maria Consolacion, Canto Alvarez Carles, Cardinale Daniele A, Cardoso Luiza HD, Carvalho Eugenia, Casado Pinna Marta, Cassar Samantha, Castelo Rueda Maria Paulina, Castilho Roger F, Cavalcanti-de-Albuquerque Joao Paulo, Cecatto Cristiane, Celen Murat C, Cervinkova Zuzana, Chabi Beatrice, Chakrabarti Lisa, Chakrabarti Sasanka, Chaurasia Bhagirath, Chen Quan, Chicco Adam J, Chinopoulos Christos, Chowdhury Subir Kumar, Cizmarova Beata, Clementi Emilio, Coen Paul M, Cohen Bruce H, Coker Robert H, Collin-Chenot Anne, Coughlan Melinda T, Coxito Pedro, Crisostomo Luis, Crispim Marcell, Crossland Hannah, Dahdah Norma Ramon, Dalgaard Louise T, Dambrova Maija, Danhelovska Tereza, Darveau Charles-A, Darwin Paula M, Das Anibh Martin, Dash Ranjan K, Davidova Eliska, Davis Michael S, Dayanidhi Sudarshan, De Bem Andreza Fabro, De Goede Paul, De Palma Clara, De Pinto Vito, Dela Flemming, Dembinska-Kiec Aldona, Detraux Damian, Devaux Yvan, Di Marcello Marco, Di Paola Floriana Jessica, Dias Candida, Dias Tania R, Diederich Marc, Distefano Giovanna, Djafarzadeh Siamak, Doermann Niklas, Doerrier Carolina, Dong Lan-Feng, Donnelly Chris, Drahota Zdenek, Duarte Filipe Valente, Dubouchaud Herve, Duchen Michael R, Dumas Jean-Francois, Durham William J, Dymkowska Dorota, Dyrstad Sissel E, Dyson Alex, Dzialowski Edward M, Eaton Simon, Ehinger Johannes K, Elmer Eskil, Endlicher Rene, Engin Ayse Basak, Escames Germaine, Evinova Andrea, Ezrova Zuzana, Falk Marni J, Fell David A, Ferdinandy Peter, Ferko Miroslav, Fernandez-Ortiz Marisol, Fernandez-Vizarra Erika, Ferreira Julio Cesar B, Ferreira Rita Maria P, Ferri Alessandra, Fessel Joshua Patrick, Festuccia William T, Filipovska Aleksandra, Fisar Zdenek, Fischer Christine, Fischer Michael J, Fisher Gordon, Fisher Joshua J, Fontanesi Flavia, Forbes-Hernandez Tamara Y, Ford Ellen, Fornaro Mara, Fuertes Agudo Marina, Fulton Montana, Galina Antonio, Galkin Alexander, Gallee Leon, Galli Gina L J, Gama Perez Pau, Gan Zhenji, Ganetzky Rebecca, Gao Yun, Garcia Geovana S, Garcia-Rivas Gerardo, Garcia-Roves Pablo Miguel, Garcia-Souza Luiz F, Garlid Keith D, Garrabou Gloria, Garten Antje, Gastaldelli Amalia, Gayen Jiaur, Genders Amanda J, Genova Maria Luisa, Giampieri Francesca, Giovarelli Matteo, Glatz Jan FC, Goikoetxea Usandizaga Naroa, Goncalo Teixeira da Silva Rui, Goncalves Debora Farina, Gonzalez- Armenta Jenny L, Gonzalez-Franquesa Alba, Gonzalez-Freire Marta, Gonzalo Hugo, Goodpaster Bret H, Gorr Thomas A, Gourlay Campbell W, Grams Bente, Granata Cesare, Grefte Sander, Grilo Luis, Guarch Meritxell Espino, Gueguen Naig, Gumeni Sentiljana, Haas Clarissa, Haavik Jan, Hachmo Yafit, Haendeler Judith, Haider Markus, Hajrulahovic Anesa, Hamann Andrea, Han Jin, Han Woo Hyun, Hancock Chad R, Hand Steven C, Handl Jiri, Hansikova Hana, Hardee Justin P, Hargreaves Iain P, Harper Mary- Ellen, Harrison David K, Hassan Hazirah, Hatokova Zuzana, Hausenloy Derek J, Heales Simon JR, Hecker Matthias, Heiestad Christina, Hellgren Kim T, Henrique Alexandrino, Hepple Russell T, Hernansanz- Agustin Pablo, Hewakapuge Sudinna, Hickey Anthony J, Ho Dieu Hien, Hoehn Kyle L, Hoel Fredrik, Holland Olivia J, Holloway Graham P, Holzner Lorenz, Hoppel Charles L, Hoppel Florian, Hoppeler Hans, Houstek Josef, Huete-Ortega Maria, Hyrossova Petra, Iglesias-Gonzalez Javier, Indiveri Cesare, Irving Brian A, Isola Raffaella, Iyer Shilpa, Jackson Christopher Benjamin, Jadiya Pooja, Jana Prado Fabian, Jandeleit-Dahm Karin, Jang David H, Jang Young Charles, Janowska Joanna, Jansen Kirsten M, Jansen-Duerr Pidder, Jansone Baiba, Jarmuszkiewicz Wieslawa, Jaskiewicz Anna, Jaspers Richard T, Jedlicka Jan, Jerome Estaquier, Jespersen Nichlas Riise, Jha Rajan Kumar, Jones John G, Joseph Vincent, Juhasz Laszlo, Jurczak Michael J, Jurk Diana, Jusic Amela, Kaambre Tuuli, Kaczor Jan Jacek, Kainulainen Heikki, Kampa Rafal Pawel, Kandel Sunil Mani, Kane Daniel A, Kapferer Werner, Kapnick Senta, Kappler Lisa, Karabatsiakis Alexander, Karavaeva Iuliia, Karkucinska-Wieckowska Agnieszka, Kaur Sarbjot, Keijer Jaap, Keller Markus A, Keppner Gloria, Khamoui Andy V, Kidere Dita, Kilbaugh Todd, Kim Hyoung Kyu, Kim Julian KS, Kimoloi Sammy, Klepinin Aleksandr, Klepinina Lyudmila, Klingenspor Martin, Klocker Helmut, Kolassa Iris, Komlodi Timea, Koopman Werner JH, Kopitar-Jerala Natasa, Kowaltowski Alicia J, Kozlov Andrey V, Krajcova Adela, Krako Jakovljevic Nina, Kristal Bruce S, Krycer James R, Kuang Jujiao, Kucera Otto, Kuka Janis, Kwak Hyo Bum, Kwast Kurt E, Kwon Oh Sung, Laasmaa Martin, Labieniec-Watala Magdalena, Lagarrigue Sylviane, Lai Nicola, Lalic Nebojsa M, Land John M, Lane Nick, Laner Verena, Lanza Ian R, Laouafa Sofien, Laranjinha Joao, Larsen Steen, Larsen Terje S, Lavery Gareth G, Lazou Antigone, Ledo Ana Margarida, Lee Hong Kyu, Leeuwenburgh Christiaan, Lehti Maarit, Lemieux Helene, Lenaz Giorgio, Lerfall Joergen, Li Pingan Andy, Li Puma Lance, Liang Liping, Liepins Edgars, Lin Chien-Te, Liu Jiankang, Lopez Garcia Luis Carlos, Lucchinetti Eliana, Ma Tao, Macedo Maria Paula, Machado Ivo F, Maciej Sarah, MacMillan-Crow Lee Ann, Magalhaes Jose, Magri Andrea, Majtnerova Pavlina, Makarova Elina, Makrecka-Kuka Marina, Malik Afshan N, Marcouiller Francois, Marechal Amandine, Markova Michaela, Markovic Ivanka, Martin Daniel S, Martins Ana Dias, Martins Joao D, Maseko Tumisang Edward, Maull Felicia, Mazat Jean-Pierre, McKenna Helen T, McKenzie Matthew, McMillan Duncan GG, McStay Gavin P, Mendham Amy, Menze Michael A, Mercer John R, Merz Tamara, Messina Angela, Meszaros Andras, Methner Axel, Michalak Slawomir, Mila Guasch Maria, Minuzzi Luciele M, Misirkic Marjanovic Maja, Moellering Douglas R, Moisoi Nicoleta, Molina Anthony JA, Montaigne David, Moore Anthony L, Moore Christy, Moreau Kerrie, Moreira Bruno P, Moreno-Sanchez Rafael, Mracek Tomas, Muccini Anna Maria, Munro Daniel, Muntane Jordi, Muntean Danina M, Murray Andrew James, Musiol Eva, Nabben Miranda, Nair K Sreekumaran, Nehlin Jan O, Nemec Michal, Nesci Salvatore, Neufer P Darrell, Neuzil Jiri, Neviere Remi, Newsom Sean A, Norman Jennifer, Nozickova Katerina, Nunes Sara, Nuoffer Jean-Marc, O'Brien Kristin, O'Brien Katie A, O'Gorman Donal, Olgar Yusuf, Oliveira Ben, Oliveira Jorge, Oliveira Marcus F, Oliveira Marcos Tulio, Oliveira Pedro Fontes, Oliveira Paulo J, Olsen Rolf Erik, Orynbayeva Zulfiya, Osiewacz Heinz D, Paez Hector, Pak Youngmi Kim, Pallotta Maria Luigia, Palmeira Carlos, Parajuli Nirmala, Passos Joao F, Passrugger Manuela, Patel Hemal H, Pavlova Nadia, Pavlovic Kasja, Pecina Petr, Pedersen Tina M, Perales Jose Carles, Pereira da Silva Grilo da Silva Filomena, Pereira Rita, Pereira Susana P, Perez Valencia Juan Alberto, Perks Kara L, Pesta Dominik, Petit Patrice X, Pettersen Nitschke Ina Katrine, Pichaud Nicolas, Pichler Irene, Piel Sarah, Pietka Terri A, Pinho Sonia A, Pino Maria F, Pirkmajer Sergej, Place Nicolas, Plangger Mario, Porter Craig, Porter Richard K, Preguica Ines, Prigione Alessandro, Procaccio Vincent, Prochownik Edward V, Prola Alexandre, Pulinilkunnil Thomas, Puskarich Michael A, Puurand Marju, Radenkovic Filip, Ramzan Rabia, Rattan Suresh IS, Reano Simone, Reboredo-Rodriguez Patricia, Rees Bernard B, Renner-Sattler Kathrin, Rial Eduardo, Robinson Matthew M, Roden Michael, Rodrigues Ana Sofia, Rodriguez Enrique, Rodriguez-Enriquez Sara, Roesland Gro Vatne, Rohlena Jakub, Rolo Anabela Pinto, Ropelle Eduardo R, Roshanravan Baback, Rossignol Rodrigue, Rossiter Harry B, Rousar Tomas, Rubelj Ivica, Rybacka-Mossakowska Joanna, Saada Reisch Ann, Safaei Zahra, Salin Karine, Salvadego Desy, Sandi Carmen, Saner Nicholas, Santos Diana, Sanz Alberto, Sardao Vilma, Sarlak Saharnaz, Sazanov Leonid A, Scaife Paula, Scatena Roberto, Schartner Melanie, Scheibye-Knudsen Morten, Schilling Jan M, Schlattner Uwe, Schmitt Sabine, Schneider Gasser Edith Mariane, Schoenfeld Peter, Schots Pauke C, Schulz Rainer, Schwarzer Christoph, Scott Graham R, Selman Colin, Sendon Pamella Marie, Shabalina Irina G, Sharma Pushpa, Sharma Vipin, Shevchuk Igor, Shirazi Reza, Shiroma Jonathan G, Siewiera Karolina, Silber Ariel M, Silva Ana Maria, Sims Carrie A, Singer Dominique, Singh Brijesh Kumar, Skolik Robert A, Smenes Benedikte Therese, Smith James, Soares Felix Alexandre Antunes, Sobotka Ondrej, Sokolova Inna, Solesio Maria E, Soliz Jorge, Sommer Natascha, Sonkar Vijay K, Sova Marina, Sowton Alice P, Sparagna Genevieve C, Sparks Lauren M, Spinazzi Marco, Stankova Pavla, Starr Jonathan, Stary Creed, Stefan Eduard, Stelfa Gundega, Stepto Nigel K, Stevanovic Jelena, Stiban Johnny, Stier Antoine, Stocker Roland, Storder Julie, Sumbalova Zuzana, Suomalainen Anu, Suravajhala Prashanth, Svalbe Baiba, Swerdlow Russell H, Swiniuch Daria, Szabo Ildiko, Szewczyk Adam, Szibor Marten, Tanaka Masashi, Tandler Bernard, Tarnopolsky Mark A, Tausan Daniel, Tavernarakis Nektarios, Teodoro Joao Soeiro, Tepp Kersti, Thakkar Himani, Thapa Maheshwor, Thyfault John P, Tomar Dhanendra, Ton Riccardo, Torp May-Kristin, Torres-Quesada Omar, Towheed Atif, Treberg Jason R, Tretter Laszlo, Trewin Adam J, Trifunovic Aleksandra, Trivigno Catherine, Tronstad Karl Johan, Trougakos Ioannis P, Truu Laura, Tuncay Erkan, Turan Belma, Tyrrell Daniel J, Urban Tomas, Urner Sofia, Valentine Joseph Marco, Van Bergen Nicole J, Van der Ende Miranda, Varricchio Frederick, Vaupel Peter, Vella Joanna, Vendelin Marko, Vercesi Anibal E, Verdaguer Ignasi Bofill, Vernerova Andrea, Victor Victor Manuel, Vieira Ligo Teixeira Camila, Vidimce Josif, Viel Christian, Vieyra Adalberto, Vilks Karlis, Villena Josep A, Vincent Vinnyfred, Vinogradov Andrey D, Viscomi Carlo, Vitorino Rui Miguel Pinheiro, Vlachaki Walker Julia, Vogt Sebastian, Volani Chiara, Volska Kristine, Votion Dominique-Marie, Vujacic-Mirski Ksenija, Wagner Brett A, Ward Marie Louise, Warnsmann Verena, Wasserman David H, Watala Cezary, Wei Yau-Huei, Weinberger Klaus M, Weissig Volkmar, White Sarah Haverty, Whitfield Jamie, Wickert Anika, Wieckowski Mariusz R, Wiesner Rudolf J, Williams Caroline M, Winwood-Smith Hugh, Wohlgemuth Stephanie E, Wohlwend Martin, Wolff Jonci Nikolai, Wrutniak-Cabello Chantal, Wuest Rob CI, Yokota Takashi, Zablocki Krzysztof, Zanon Alessandra, Zanou Nadege, Zaugg Kathrin, Zaugg Michael, Zdrazilova Lucie, Zhang Yong, Zhang Yizhu, Zikova Alena, Zischka Hans, Zorzano Antonio, Zujovic Tijana, Zurmanova Jitka, Zvejniece Liga

Subjects
uncoupling, MitoPedia: Respiratory states, SI - The International System of Units, IUPAC, Coupling control, Mitochondrial preparations, Protonmotive force, Uncoupling, Oxidative phosphorylation, Phosphorylation efficiency, Electron transfer-pathway, LEAK-respiration, Residual oxygen consumption, Normalization of rate, Flow, Flux, Flux control ratio, Mitochondrial marker, Cell count, Oxygen, [SDV]Life Sciences [q-bio], coupling control, protonmotive force, oxidative phosphorylation, mitochondrial respiratory control, State 4, electron transfer, State 2, State 3, Mitochondrial physiology, residual oxygen consumption, flux, normalization, ion leak and slip compensatory state, efficiency, electron transfer system, flow, mitochondrial physiology, oxygen, mitochondrial preparations, proton leak
Abstract

As the knowledge base and importance of mitochondrial physiology to evolution, health and diseaseexpands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followthe latest SI guidelines and those of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute BEC 2020.1 doi:10.26124/bec:2020-0001.v1www.bioenergetics-communications.org3of 44to reproducibility between laboratories and thussupport the development of datarepositoriesof mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.

Published
2020
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34. PGC-1α and MEF2 Regulate the Transcription of the Carnitine Transporter OCTN2 Gene in C2C12 Cells and in Mouse Skeletal Muscle.

Author

Novakova, Katerina, Török, Michael, Panajatovic, Miljenko, Bouitbir, Jamal, Duong, François H. T., Handschin, Christoph, and Krähenbühl, Stephan

Subjects
SKELETAL muscle, CARNITINE, KNOCKOUT mice, BINDING sites, GENE expression, MYOBLASTS
Abstract

OCTN2 (SLC22A5) is a carnitine transporter whose main function is the active transport of carnitine into cells. In skeletal muscle and other organs, the regulation of the SLC22A5 gene transcription has been shown to depend on the nuclear transcription factor PPAR-α. Due to the observation that the muscle OCTN2 mRNA level is maintained in PPAR-α knock-out mice and that PGC-1α overexpression in C2C12 myoblasts increases OCTN2 mRNA expression, we suspected additional regulatory pathways for SLC22A5 gene transcription. Indeed, we detected several binding sites of the myocyte-enhancing factor MEF2 in the upstream region of the SLC22A5 gene, and MEF2C/MEF2D stimulated the activity of the OCTN2 promoter in gene reporter assays. This stimulation was increased by PGC-1α and was blunted for a SLC22A5 promoter fragment with a mutated MEF2 binding site. Further, we demonstrated the specific binding of MEF2 to the SLC22A5 gene promoter, and a supershift of the MEF2/DNA complex in electrophoretic mobility shift assays. In immunoprecipitation experiments, we could demonstrate the interaction between PGC-1α and MEF2. In addition, SB203580, a specific inhibitor of p38 MAPK, blocked and interferon-γ stimulated the transcriptional activity of the SLC22A5 gene promoter. Finally, mice with muscle-specific overexpression of OCTN2 showed an increase in OCTN2 mRNA and protein expression in skeletal muscle. In conclusion, we detected and characterized a second stimulatory pathway of SLC22A5 gene transcription in skeletal muscle, which involves the nuclear transcription factor MEF2 and co-stimulation by PGC-1α and which is controlled by the p38 MAPK signaling cascade. [ABSTRACT FROM AUTHOR]

Published
2022
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41. Implication of Lipids in Calcified Aortic Valve Pathogenesis: Why Did Statins Fail?

Author

Nsaibia, Mohamed J., Devendran, Anichavezhi, Goubaa, Eshak, Bouitbir, Jamal, Capoulade, Romain, and Bouchareb, Rihab

Subjects
AORTIC valve, AORTIC valve diseases, DYSLIPIDEMIA, LIPIDS, AORTIC stenosis, LDL cholesterol
Abstract

Calcific Aortic Valve Disease (CAVD) is a fibrocalcific disease. Lipoproteins and oxidized phospholipids play a substantial role in CAVD; the level of Lp(a) has been shown to accelerate the progression of valve calcification. Indeed, oxidized phospholipids carried by Lp(a) into the aortic valve stimulate endothelial dysfunction and promote inflammation. Inflammation and growth factors actively promote the synthesis of the extracellular matrix (ECM) and trigger an osteogenic program. The accumulation of ECM proteins promotes lipid adhesion to valve tissue, which could initiate the osteogenic program in interstitial valve cells. Statin treatment has been shown to have the ability to diminish the death rate in subjects with atherosclerotic impediments by decreasing the serum LDL cholesterol levels. However, the use of HMG-CoA inhibitors (statins) as cholesterol-lowering therapy did not significantly reduce the progression or the severity of aortic valve calcification. However, new clinical trials targeting Lp(a) or PCSK9 are showing promising results in reducing the severity of aortic stenosis. In this review, we discuss the implication of lipids in aortic valve calcification and the current findings on the effect of lipid-lowering therapy in aortic stenosis. [ABSTRACT FROM AUTHOR]

Published
2022
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44. Comparative Effects of Metamizole (Dipyrone) and Naproxen on Renal Function and Prostacyclin Synthesis in Salt-Depleted Healthy Subjects - A Randomized Controlled Parallel Group Study.

Author

Blaser, Lea S, Duthaler, Urs, Bouitbir, Jamal, Leuppi-Taegtmeyer, Anne B, Liakoni, Evangelia, Dolf, Reto, Mayr, Michael, Drewe, Jürgen, Krähenbühl, Stephan, and Haschke, Manuel

Subjects
INULIN, KIDNEY physiology, SALT-free diet, NAPROXEN, PROSTACYCLIN, DIPYRONE
Abstract

Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α. Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing. Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC50 0.69 ± 0.27 µM) compared with naproxen (EC50 0.034 ± 0.033 µM). Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis. [ABSTRACT FROM AUTHOR]

Published
2021
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45. Mechanisms of Hepatocellular Toxicity Associated with Dronedarone—A Comparison to Amiodarone

Author

Felser, Andrea, Blum, Kim, Lindinger, Peter W., Bouitbir, Jamal, and Krähenbühl, Stephan

Abstract

Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50µM, respectively. The cellular ATP content started to decrease at 20µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10µM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidation at 10µM and amiodarone at 20µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo

Published
2017

46. Imatinib and Dasatinib Provoke Mitochondrial Dysfunction Leading to Oxidative Stress in C2C12 Myotubes and Human RD Cells.

Author

Bouitbir, Jamal, Panajatovic, Miljenko Valentin, Frechard, Theo, Roos, Noëmi Johanna, and Krähenbühl, Stephan

Subjects
DASATINIB, IMATINIB, OXIDATIVE stress, REACTIVE oxygen species, PROTEIN-tyrosine kinases
Abstract

Tyrosine kinase inhibitors (TKIs) can cause skeletal muscle toxicity in patients, but the underlying mechanisms are mostly unclear. The goal of the current study was to better characterize the role of mitochondria in TKI-associated myotoxicity. We exposed C2C12 murine myoblasts and myotubes as well as human rhabdomyosarcoma cells (RD cells) for 24 h to imatinib (1–100 µM), erlotinib (1–20 µM), and dasatinib (0.001–100 µM). In C2C12 myoblasts, imatinib was membrane toxic at 50 µM and depleted the cellular ATP pool at 20 µM. In C2C12 myotubes exposed to imatinib, ATP depletion started at 50 µM whereas membrane toxicity was not detectable. In myoblasts and myotubes exposed to dasatinib, membrane toxicity started at 0.5 µM and 2 µM, respectively, and the ATP drop was visible at 0.1 µM and 0.2 µM, respectively. When RD cells were exposed to imatinib, ATP depletion started at 20 µM whereas membrane toxicity was not detectable. Dasatinib was membrane toxic at 20 µM and depleted the cellular ATP pool already at 0.5 µM. Erlotinib was not toxic in both cell models. Imatinib (20 µM) and dasatinib (1 µM) reduced complex I activity in both cell models. Moreover, the mitochondrial membrane potential (Δψ m) was dissipated for both TKIs in myotubes. In RD cells, the Δψ m was reduced only by dasatinib. Both TKIs increased mitochondrial superoxide accumulation and decreased the mitochondrial copy number in both cell lines. In consequence, they increased protein expression of superoxide dismutase (SOD) 2 and thioredoxin 2 and cleavage of caspase 3, indicating apoptosis in C2C12 myotubes. Moreover, in both cell models, the mRNA expression of Sod1 and Sod2 increased when RD cells were exposed to dasatinib. Furthermore, dasatinib increased the mRNA expression of atrogin-1 and murf-1 , which are important transcription factors involved in muscle atrophy. The mRNA expression of atrogin-1 increased also in RD cells exposed to imatinib. In conclusion, imatinib and dasatinib are mitochondrial toxicants in mouse C2C12 myotubes and human RD cells. Mitochondrial superoxide accumulation induced by these two TKIs is due to the inhibition of complex I and is probably related to impaired mitochondrial and myocyte proliferation. [ABSTRACT FROM AUTHOR]

Published
2020
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47. Lapatinib Activates the Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 Pathway in HepG2 Cells.

Author

Roos, Noëmi Johanna, Aliu, Diell, Bouitbir, Jamal, and Krähenbühl, Stephan

Subjects
LAPATINIB, PROTHROMBIN, MITOCHONDRIAL proteins, PROTEIN-tyrosine kinases, TRANSCRIPTION factors, CYTOPROTECTION, GLUTATHIONE
Abstract

The receptor tyrosine kinase inhibitor lapatinib, indicated to treat patients with HER2-positive breast cancer in combination with capecitabine, can cause severe hepatotoxicity. Lapatinib is further associated with mitochondrial toxicity and accumulation of reactive oxygen species. The effect of lapatinib on the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, the major cellular defense pathway against oxidative stress, has so far not been studied in detail. In the present study, we show that lapatinib (2–20 µM) activates the Keap1-Nrf2 pathway in HepG2 cells, a hepatocellular carcinoma-derived cell line, in a concentration-dependent manner upon 24 h of treatment. Lapatinib stabilized the transcription factor Nrf2 at concentrations ≥5 µM and caused its nuclear translocation. Well-established Nrf2 regulated genes (Nqo1 , Gsta1 , Gclc , and Gclm) were upregulated at lapatinib concentrations ≥10 µM. Furthermore, cellular and mitochondrial glutathione (GSH) levels increased starting at 10 µM lapatinib. As a marker of oxidative stress, cellular GSSG significantly increased at 10 and 20 µM lapatinib. Furthermore, the gene expression of mitochondrial Glrx2 and SOD2 were increased upon lapatinib treatment, which was also observed for the mitochondrial SOD2 protein content. In conclusion, lapatinib treatment for 24 h activated the Keap1-Nrf2 pathway in HepG2 cells starting at 10 μM, which is a clinically relevant concentration. As a consequence, treatment with lapatinib increased the mRNA and protein expression of antioxidative and other cytoprotective genes and induced GSH synthesis, but these measures could not completely block the oxidative stress associated with lapatinib. [ABSTRACT FROM AUTHOR]

Published
2020
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48. PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice.

Author

Panajatovic, Miljenko Valentin, Singh, François, Roos, Noëmi Johanna, Duthaler, Urs, Handschin, Christoph, Krähenbühl, Stephan, and Bouitbir, Jamal

Subjects
CITRATE synthase, MITOCHONDRIAL DNA, MICE, GRIP strength, LONG-distance running, LACTATES
Abstract

Aim: Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC‐1α in statin‐associated myotoxicity. Methods: We treated PGC‐1α knockout (KO), PGC‐1α overexpression (OE) and wild‐type (WT) mice orally with 5 mg simvastatin kg−1 day−1 for 3 weeks and assessed muscle function and metabolism. Results: In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post‐exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice. Conclusions: Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC‐1α in preventing simvastatin‐associated myotoxicity. [ABSTRACT FROM AUTHOR]

Published
2020
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49. Muscles Susceptibility to Ischemia-Reperfusion Injuries Depends on Fiber Type Specific Antioxidant Level

Author

Charles, Anne-Laure, Guilbert, Anne-Sophie, Guillot, Max, Talha, Samy, Lejay, Anne, Meyer, Alain, Kindo, Michel, Wolff, Valérie, Bouitbir, Jamal, Zoll, Joffrey, and Geny, Bernard

Subjects
mitochondria, sarcopenia, antioxidant, Physiology, muscle, Physiology (medical), metabolic phenotype, oxidative stress, peripheral arterial disease (PAD), ischemia-reperfusion
Abstract

Muscle injury resulting from ischemia-reperfusion largely aggravates patient prognosis but whether and how muscle phenotype modulates ischemia-reperfusion-induced mitochondrial dysfunction remains to be investigated. We challenged the hypothesis that glycolytic muscles are more prone to ischemia-reperfusion-induced injury than oxidative skeletal muscles. We therefore determined simultaneously the effect of 3 h of ischemia induced by aortic clamping followed by 2 h of reperfusion (IR, n = 11) on both gastrocnemius and soleus muscles, as compared to control animals (C, n = 11). Further, we investigated whether tempol, an antioxidant mimicking superoxide dismutase, might compensate a reduced defense system, likely characterizing glycolytic muscles (IR-Tempol, n = 7). In the glycolytic gastrocnemius muscle, as compared to control, ischemia-reperfusion significantly decreased mitochondrial respiration (−30.28 ± 6.16%, p = 0.003), increased reactive oxygen species production (+79.15 ± 28.72%, p = 0.04), and decreased reduced glutathione (−28.19 ± 6.80%, p = 0.011). Less deleterious effects were observed in the oxidative soleus muscle (−6.44 ± 6.30%, +4.32 ± 16.84%, and −8.07 ± 10.84%, respectively), characterized by enhanced antioxidant defenses (0.63 ± 0.05 in gastrocnemius vs. 1.24 ± 0.08 μmol L−1 g−1 in soleus). Further, when previously treated with tempol, glycolytic muscle was largely protected against the deleterious effects of ischemia-reperfusion. Thus, oxidative skeletal muscles are more protected than glycolytic ones against ischemia-reperfusion, thanks to their antioxidant pool. Such pivotal data support that susceptibility to ischemia-reperfusion-induced injury differs between organs, depending on their metabolic phenotypes. This suggests a need to adapt therapeutic strategies to the specific antioxidant power of the target organ to be protected.

Published
2017
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50. Hepatotoxicity Due to Azole Antimycotic Agents in a HLA B*35:02-Positive Patient.

Author

Bühler, Tim, Medinger, Michael, Bouitbir, Jamal, Krähenbühl, Stephan, and Leuppi-Taegtmeyer, Anne

Subjects
HEPATOTOXICOLOGY, HEMATOPOIETIC stem cell transplantation, ANTIFUNGAL agents, PULMONARY aspergillosis, ACUTE myeloid leukemia, THERAPEUTICS
Abstract

We will present a 42-year-old woman with acute myeloid leukemia and pulmonary aspergillosis. She was treated with several antifungal agents, including three triazoles. Voriconazole, posaconazole, and isavuconazole all led to hepatocellular liver injury. Voriconazole administration led to a peak alanine aminotransferase (ALT) value of 1,793 U/L (normal range, 9–59 U/L). After posaconazole and isavuconazole treatment, ALT rose over 500 U/L. The typical course of events, exclusion of differential diagnoses, and normalization of the liver function tests (LFTs) after stopping the triazoles were highly suspicious for a drug-induced liver injury (DILI). Interestingly, our patient carries a rare HLA B allele (HLA B*35:02), which occurs in less than 1% of the population and is known to be associated with minocycline-induced liver injury. Over the course of 4 months, the patient received two induction chemotherapies and afterward underwent a successful allogenic hematopoietic stem cell transplantation. Her liver function recovered rapidly and favorable clinical findings concerning the aspergillosis led to a de-escalation of the antifungal treatment to prophylactic dose fluconazole. Delayed hepatotoxicity suggested a dose dependency and a cumulative effect. The question of a common pathophysiology and a cross-toxicity was raised. At the present time, only a few case reports describe cross-toxicity or its absence after rechallenge with different azoles. The pathophysiology is not well understood. Ketoconazole was found to impair rat mitochondrial function in vitro. Further investigations showed cell membrane toxicity and ATP depletion in isolated human liver cancer cells. Our case report suggests a cross-toxicity, dose-dependency, and a possible genetic predisposition of triazole-induced liver injury. [ABSTRACT FROM AUTHOR]

Published
2019
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