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1. Mitochondrial respiratory states and rate

Author

Gnaiger, E., Aasander Frostner, E., Abdul Karim, N., Abumrad, NA., Acuna-Castroviejo, D., Adiele, RC., Ahn, B., Ali, SS., Alton, L., Alves, MG., Amati, F., Amoedo, ND., Andreadou, I., Arago, M., Aral, C., Arandarcikaite, O., Armand, AS., Arnould, T., Avram, VF., Bailey, DM., Bajpeyi, S., Bajzikova, M., Bakker, BM., Barlow, J., Bastos Sant'Anna Silva, AC., Batterson, P., Battino, M., Bazil, J., Beard, DA., Bednarczyk, P., Bello, F., Ben-Shachar, D., Bergdahl, A., Berge, RK., Bergmeister, L., Bernardi, P., Berridge, MV., Bettinazzi, S., Bishop, D., Blier, PU., Blindheim, DF., Boardman, NT., Boetker, HE., Borchard, S., Boros, M., Borsheim, E., Borutaite, V., Botella, J., Bouillaud, F., Bouitbir, J., Boushel, RC., Bovard, J., Breton, S., Brown, DA., Brown, GC., Brown, RA., Brozinick, JT., Buettner, GR., Burtscher, J., Calabria, E., Calbet, JA., Calzia, E., Cannon, DT., Cano Sanchez, M., Canto, AC., Cardoso, LHD., Carvalho, E., Casado Pinna, M., Cassar, S., Cassina, AM., Castelo, MP., Castro, L., Cavalcanti-de-Albuquerque, JP., Cervinkova, Z., Chabi, B., Chakrabarti, L., Chakrabarti, S., Chaurasia, B., Chen, Q., Chicco, AJ., Chinopoulos, C., Chowdhury, SK., Cizmarova, B., Clementi, E., Coen, PM., Cohen, BH., Coker, RH., Collin, A., Crisostomo, L., Dahdah, N., Dalgaard, LT., Dambrova, M., Danhelovska, T., Darveau, CA., Das, AM., Dash, RK., Davidova, E., Davis, MS., De Goede, P., De Palma, C., Dembinska-Kiec, A., Detraux, D., Devaux, Y., Di Marcello, M., Dias, TR., Distefano, G., Doermann, N., Doerrier, C., Dong, L., Donnelly, C., Drahota, Z., Duarte, FV., Dubouchaud, H., Duchen, MR., Dumas, JF., Durham, WJ., Dymkowska, D., Dyrstad, SE., Dyson, A., Dzialowski, EM., Eaton, S., Ehinger, J., Elmer, E., Endlicher, R., Engin, AB., Escames, G., Ezrova, Z., Falk, MJ., Fell, DA., Ferdinandy, P., Ferko, M., Ferreira, JCB., Ferreira, R., Ferri, A., Fessel, JP., Filipovska, A., Fisar, Z., Fischer, C., Fischer, M., Fisher, G., Fisher, JJ., Ford, E., Fornaro, M., Galina, A., Galkin, A., Gallee, L., Galli, GL., Gama Perez, P., Gan, Z., Ganetzky, R., Garcia-Rivas, G., Garcia-Roves, PM., Garcia-Souza, LF., Garipi, E., Garlid, KD., Garrabou, G., Garten, A., Gastaldelli, A., Gayen, J., Genders, AJ., Genova, ML., Giovarelli, M., Goncalo Teixeira da Silva, R., Goncalves, DF., Gonzalez-Armenta, JL., Gonzalez-Freire, M., Gonzalo, H., Goodpaster, BH., Gorr, TA., Gourlay, CW., Granata, C., Grefte, S., Guarch, ME., Gueguen, N., Gumeni, S., Haas, CB., Haavik, J., Haendeler, J., Haider, M., Hamann, A., Han, J., Han, WH., Hancock, CR., Hand, SC., Handl, J., Hargreaves, IP., Harper, ME., Harrison, DK., Hassan, H., Hausenloy, DJ., Heales, SJR., Heiestad, C., Hellgren, KT., Hepple, RT., Hernansanz-Agustin, P., Hewakapuge, S., Hickey, AJ., Ho, DH., Hoehn, KL., Hoel, F., Holland, OJ., Holloway, GP., Hoppel, CL., Hoppel, F., Houstek, J., Huete-Ortega, M., Hyrossova, P., Iglesias-Gonzalez, J., Irving, BA., Isola, R., Iyer, S., Jackson, CB., Jadiya, P., Jana, PF., Jang, DH., Jang, YC., Janowska, J., Jansen, K., Jansen-Duerr, P., Jansone, B., Jarmuszkiewicz, W., Jaskiewicz, A., Jedlicka, J., Jespersen, NR., Jha, RK., Jurczak, MJ., Jurk, D., Kaambre, T., Kaczor, JJ., Kainulainen, H., Kampa, RP., Kandel, SM., Kane, DA., Kapferer, W., Kappler, L., Karabatsiakis, A., Karavaeva, I., Karkucinska-Wieckowska, A., Kaur, S., Keijer, J., Keller, MA., Keppner, G., Khamoui, AV., Kidere, D., Kilbaugh, T., Kim, HK., Kim, JKS., Klepinin, A., Klepinina, L., Klingenspor, M., Klocker, H., Komlodi, T., Koopman, WJH., Kopitar-Jerala, N., Kowaltowski, AJ., Kozlov, AV., Krajcova, A., Krako Jakovljevic, N., Kristal, BS., Krycer, JR., Kuang, J., Kucera, O., Kuka, J., Kwak, HB., Kwast, K., Laasmaa, M., Labieniec-Watala, M., Lagarrigue, S., Lai, N., Land, JM., Lane, N., Laner, V., Lanza, IR., Laranjinha, J., Larsen, TS., Lavery, GG., Lazou, A., Lee, HK., Leeuwenburgh, C., Lehti, M., Lemieux, H., Lenaz, G., Lerfall, J., Li, PA., Li Puma, L., Liepins, E., Liu, J., Lopez, LC., Lucchinetti, E., Ma, T., Macedo, MP., Maciej, S., MacMillan-Crow, LA., Majtnerova, P., Makarova, E., Makrecka-Kuka, M., Malik, AN., Markova, M., Martin, DS., Martins, AD., Martins, JD., Maseko, TE., Maull, F., Mazat, JP., McKenna, HT., McKenzie, M., Menze, MA., Merz, T., Meszaros, AT., Methner, A., Michalak, S., Moellering, DR., Moisoi, N., Molina, AJA., Montaigne, D., Moore, AL., Moreau, K., Moreira, BP., Moreno-Sanchez, R., Mracek, T., Muccini, AM., Munro, D., Muntane, J., Muntean, DM., Murray, AJ., Musiol, E., Nabben, M., Nair, KS., Nehlin, JO., Nemec, M., Neufer, PD., Neuzil, J., Neviere, R., Newsom, SA., Nozickova, K., O'Brien, KA., O'Gorman, D., Olgar, Y., Oliveira, B., Oliveira, MF., Oliveira, MT., Oliveira, PF., Oliveira, PJ., Orynbayeva, Z., Osiewacz, HD., Pak, YK., Pallotta, ML., Palmeira, CM., Parajuli, N., Passos, JF., Passrugger, M., Patel, HH., Pavlova, N., Pecina, P., Pedersen, TM., Pereira da Silva Grilo da Silva, F., Pereira, SP., Perez Valencia, JA., Perks, KL., Pesta, D., Petit, PX., Pettersen, IKN., Pichaud, N., Pichler, I., Piel, S., Pietka, TA., Pino, MF., Pirkmajer, S., Plangger, M., Porter, C., Porter, RK., Procaccio, V., Prochownik, EV., Prola, A., Pulinilkunnil, T., Puskarich, MA., Puurand, M., Radenkovic, F., Ramzan, R., Rattan, SIS., Reboredo, P., Renner-Sattler, K., Rial, E., Robinson, MM., Roden, M., Rodriguez, E., Rodriguez-Enriquez, S., Roesland, GV., Rohlena, J., Rolo, AP., Ropelle, ER., Rossignol, R., Rossiter, HB., Rubelj, I., Rybacka-Mossakowska, J., Saada, A., Safaei, Z., Saharnaz, S., Salin, K., Salvadego, D., Sandi, C., Saner, N., Sanz, A., Sazanov, LA., Scatena, R., Schartner, M., Scheibye-Knudsen, M., Schilling, JM., Schlattner, U., Schoenfeld, P., Schots, PC., Schulz, R., Schwarzer, C., Scott, GR., Selman, C., Shabalina, IG., Sharma, P., Sharma, V., Shevchuk, I., Shirazi, R., Shiroma, JG., Siewiera, K., Silber, AM., Silva, AM., Sims, CA., Singer, D., Singh, BK., Skolik, R., Smenes, BT., Smith, J., Soares, FAA., Sobotka, O., Sokolova, I., Sonkar, VK., Sowton, AP., Sparagna, GC., Sparks, LM., Spinazzi, M., Stankova, P., Starr, J., Stary, C., Stelfa, G., Stepto, NK., Stiban, J., Stier, A., Stocker, R., Storder, J., Sumbalova, Z., Suomalainen, A., Suravajhala, P., Svalbe, B., Swerdlow, RH., Swiniuch, D., Szabo, I., Szewczyk, A., Szibor, M., Tanaka, M., Tandler, B., Tarnopolsky, MA., Tausan, D., Tavernarakis, N., Tepp, K., Thakkar, H., Thapa, M., Thyfault, JP., Tomar, D., Ton, R., Torp, MK., Towheed, A., Tretter, L., Trewin, AJ., Trifunovic, A., Trivigno, C., Tronstad, KJ., Trougakos, IP., Truu, L., Tuncay, E., Turan, B., Tyrrell, DJ., Urban, T., Valentine, JM., Van Bergen, NJ., Van Hove, J., Varricchio, F., Vella, J., Vendelin, M., Vercesi, AE., Victor, VM., Vieira Ligo Teixeira, C., Vidimce, J., Viel, C., Vieyra, A., Vilks, K., Villena, JA., Vincent, V., Vinogradov, AD., Viscomi, C., Vitorino, RMP., Vogt, S., Volani, C., Volska, K., Votion, DM., Vujacic-Mirski, K., Wagner, BA., Ward, ML., Warnsmann, V., Wasserman, DH., Watala, C., Wei, YH., Whitfield, J., Wickert, A., Wieckowski, MR., Wiesner, RJ., Williams, CM., Winwood-Smith, H., Wohlgemuth, SE., Wohlwend, M., Wolff, JN., Wrutniak-Cabello, C., Wuest, RCI., Yokota, T., Zablocki, K., Zanon, A., Zanou, N., Zaugg, K., Zaugg, M., Zdrazilova, L., Zhang, Y., Zhang, YZ., Zikova, A., Zischka, H., Zorzano, A., and Zvejniece, L.

Subjects
Mitochondrial respiratory control, coupling control, mitochondrial preparations, protonmotive force, uncoupling, oxidative phosphorylation, OXPHOS, efficiency, electron transfer, ET, proton leak, LEAK, residual oxygen consumption, ROX, State 2, State 3, State 4, normalization, flow, flux, O2
Abstract

As the knowledge base and importance of mitochondrial physiology to human health expands, 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 followguidelines 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 to reproducibility between laboratories and thussupport the development of databases of 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
2019

2. Mitochondrial respiratory states and rates: Building blocks of mitochondrial physiology (Part 1)

Author

Gnaiger, E., Ahn, B., Alves, M. G., Amati, F., Aral, C., Arandarčikaitė, O., Åsander Frostner, E., Bailey, David M., Bastos Sant'Anna Silva, A. C., Battino, M., Beard, D. A., Newsom, S., Robinson, M. M., Patel, H. H., Buettner, G. R., Pecina, P., Shevchuk, I., Pereira da Silva Grilo da Silva, F., Ben-Shachar, D., Pesta, D., Goodpaster, B. H., Zorzano, Antonio, Petit, P. X., Pichaud, N., Pirkmajer, S., Porter, R. K., Wagner, B. A., Pranger, F., Rohlena, J., Prochownik, E. V., Siewiera, K., Røsland, G. V., Ehinger, J., Rossiter, H. B., Towheed, A., Rybacka-Mossakowska, J., Dias, T., Salvadego, D., Jansen-Dürr, P., Scatena, R., Schartner, M., Scheibye-Knudsen, Morten, Breton, S., Cardoso, L.H.D., Schilling, J. M., Singer, D., Schlattner, U., Brown, R. A., Sobotka, O., Spinazzi, M., Ward, M. L., Brown, G. C., Gonzalo, H., Stankova, P., Labieniec-Watala, M., Stier, A., Stocker, R., Sumbalova, Zuzana, Doerrier, C., Suravajhala, P., Tretter, L., Tanaka, M., Duchen, Michael R., Trivigno, C., Tronstad, K. J., Carvalho, Eugenia, Drahota, Z., Jackson, C. B., Trougakos, I. P., Tyrrell, D. J., Urban, T., Velika, B., Gorr, T. A., Vercesi, A. E., Watala, C., Victor, V. M., Grefte, S., Wei, Y. H., Wieckowski, M. R., O'Gorman, D., Kucera, O., Wohlwend, M., Wolff, J., Wuest, R.C.I., Zaugg, K., Jespersen, N. R., Zaugg, M., Casado, Marta, Calabria, E., Červinková, Zuzana, Chang, S. C., Radenkovic, F., Moisoi, N., Chicco, A. J., Chinopoulos, C., Coen, P. M., Collins, J. L., Lai, N., Crisóstomo, L., Elmer, E., Davis, M. S., Han, J., Endlicher, R., Pak, Y. K., Fell, D. A., Jha, R. K., Ferko, M., Nozickova, K., Ferreira, J.C.B., Scott, G. R., Filipovska, A., Fisar, Z., Fisher, J., García-Rovés, Pablo M., Molina, A.J.A., Garcia-Souza, L. F., Harrison, D. K., Genova, M. L., Kaambre, T., Hellgren, K. T., Hernansanz-Agustín, Pablo, Laner, V., Holland, O., Puurand, M., Hoppel, C. L., Tepp, K., Houstek, J., Hunger, M., Iglesias-Gonzalez, J., Oliveira, P. F., Irving, B. A., Kane, D. A., Iyer, S., Orynbayeva, Z., Kappler, L., Karabatsiakis, A., Montaigne, D., Oliveira, P. J., Schoenfeld, P., Keijer, J., Keppner, G., Komlodi, T., Kopitar-Jerala, N., Reboredo, P., Krako Jakovljevic, N., Larsen, T. S., Kuang, J., Renner-Sattler, K., Lee, H. K., Lemieux, H., Bishop, D., Tandler, B., Lerfall, J., Lucchinetti, E., MacMillan-Crow, L. A., Makrecka-Kuka, M., Shabalina, I. G., Meszaros, A. T., Moore, A. L., Michalak, S., Moreira, B. P., Mracek, T., Distefano, G., Villena, J. A., Muntané, Jordi, Muntean, D. M., Murray, A. J., Nedergaard, J., Tomar, D., Nemec, M., Palmeira, C. M., and European Commission

Subjects
Mitochondrial preparations, Mitochondrial respiratory control, Proton leak, Flux, Flow, Coupling control, Efficiency, State 4, Protonmotive force, State 2, OXPHOS, Residual oxygen consumption, State 3, Electron transfer, Normalization, ROX, Oxidative phosphorylation, LEAK, ET
Abstract

Supporting co-authors: Bakker BM, Bernardi P, Boetker HE, Borsheim E, Borutaitė V, Bouitbir J, Calbet JA, Calzia E, Chaurasia B, Clementi E, Coker RH, Collin A, Das AM, De Palma C, Dubouchaud H, Durham WJ, Dyrstad SE, Engin AB, Fornaro M, Gan Z, Garlid KD, Garten A, Gourlay CW, Granata C, Haas CB, Haavik J, Haendeler J, Hand SC, Hepple RT, Hickey AJ, Hoel F, Jang DH, Kainulainen H, Khamoui AV, Klingenspor M, Koopman WJH, Kowaltowski AJ, Krajcova A, Lane N, Lenaz G, Malik A, Markova M, Mazat JP, Menze MA, Methner A, Neuzil J, Oliveira MT, Pallotta ML, Parajuli N, Pettersen IKN, Porter C, Pulinilkunnil T, Ropelle ER, Salin K, Sandi C, Sazanov LA, Silber AM, Skolik R, Smenes BT, Soares FAA, Sokolova I, Sonkar VK, Swerdlow RH, Szabo I, Trifunovic A, Thyfault JP, Valentine JM, Vieyra A, Votion DM, Williams C, Zischka H, As the knowledge base and importance of mitochondrial physiology to human health expand, the necessity for harmonizing nomenclature concerning mitochondrial respiratory states and rates has become increasingly apparent. Clarity of concept and consistency of nomenclature are key trademarks of a research field. These trademarks facilitate effective transdisciplinary communication, education, and ultimately further discovery. Peter Mitchell’s chemiosmotic theory establishes the link between vectorial and scalar energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theory and nomenclature for mitochondrial physiology and bioenergetics. Herein, we follow IUPAC guidelines on general terms of physical chemistry, extended by considerations on open systems and irreversible thermodynamics. We align the nomenclature and symbols of classical bioenergetics with a concept-driven constructive terminology to express the meaning of each quantity clearly and consistently. In this position statement, in the frame of COST Action MitoEAGLE, we endeavour to provide a balanced view on mitochondrial 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 ultimately support the development of databases of mitochondrial respiratory function in species, tissues, and cells., We thank M. Beno for management assistance. Supported by COST Action CA15203 MitoEAGLE and K-Regio project MitoFit (E.G.).

Published
2018
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4. Mitochondrial respiratory states and rates: Building blocks of mitochondrial physiology (Part 1)

Author

European Commission, Gnaiger, E., Ahn, B., Alves, M. G., Amati, F., Aral, C., Arandarčikaitė, O., Åsander Frostner, E., Bailey, David M., Bastos Sant'Anna Silva, A. C., Battino, M., Beard, D. A., Newsom, S., Robinson, M. M., Patel, H. H., Buettner, G. R., Pecina, P., Shevchuk, I., Pereira da Silva Grilo da Silva, F., Ben-Shachar, D., Pesta, D., Goodpaster, B. H., Zorzano, Antonio, Petit, P. X., Pichaud, N., Pirkmajer, S., Porter, R. K., Wagner, B. A., Pranger, F., Rohlena, J., Prochownik, E. V., Siewiera, K., Røsland, G. V., Ehinger, J., Rossiter, H. B., Towheed, A., Rybacka-Mossakowska, J., Dias, T., Salvadego, D., Jansen-Dürr, P., Scatena, R., Schartner, M., Scheibye-Knudsen, Morten, Breton, S., Cardoso, L.H.D., Schilling, J. M., Singer, D., Schlattner, U., Brown, R. A., Sobotka, O., Spinazzi, M., Ward, M. L., Brown, G. C., Gonzalo, H., Stankova, P., Labieniec-Watala, M., Stier, A., Stocker, R., Sumbalova, Zuzana, Doerrier, C., Suravajhala, P., Tretter, L., Tanaka, M., Duchen, Michael R., Trivigno, C., Tronstad, K. J., Carvalho, Eugenia, Drahota, Z., Jackson, C. B., Trougakos, I. P., Tyrrell, D. J., Urban, T., Velika, B., Gorr, T. A., Vercesi, A. E., Watala, C., Victor, V. M., Grefte, S., Wei, Y. H., Wieckowski, M. R., O'Gorman, D., Kucera, O., Wohlwend, M., Wolff, J., Wuest, R.C.I., Zaugg, K., Jespersen, N. R., Zaugg, M., Casado, Marta, Calabria, E., Červinková, Zuzana, Chang, S. C., Radenkovic, F., Moisoi, N., Chicco, A. J., Chinopoulos, C., Coen, P. M., Collins, J. L., Lai, N., Crisóstomo, L., Elmer, E., Davis, M. S., Han, J., Endlicher, R., Pak, Y. K., Fell, D. A., Jha, R. K., Ferko, M., Nozickova, K., Ferreira, J.C.B., Scott, G. R., Filipovska, A., Fisar, Z., Fisher, J., García-Rovés, Pablo M., Molina, A.J.A., Garcia-Souza, L. F., Harrison, D. K., Genova, M. L., Kaambre, T., Hellgren, K. T., Hernansanz-Agustín, Pablo, Laner, V., Holland, O., Puurand, M., Hoppel, C. L., Tepp, K., Houstek, J., Hunger, M., Iglesias-Gonzalez, J., Oliveira, P. F., Irving, B. A., Kane, D. A., Iyer, S., Orynbayeva, Z., Kappler, L., Karabatsiakis, A., Montaigne, D., Oliveira, P. J., Schoenfeld, P., Keijer, J., Keppner, G., Komlodi, T., Kopitar-Jerala, N., Reboredo, P., Krako Jakovljevic, N., Larsen, T. S., Kuang, J., Renner-Sattler, K., Lee, H. K., Lemieux, H., Bishop, D., Tandler, B., Lerfall, J., Lucchinetti, E., MacMillan-Crow, L. A., Makrecka-Kuka, M., Shabalina, I. G., Meszaros, A. T., Moore, A. L., Michalak, S., Moreira, B. P., Mracek, T., Distefano, G., Villena, J. A., Muntané, Jordi, Muntean, D. M., Murray, A. J., Nedergaard, J., Tomar, D., Nemec, M., Palmeira, C. M., European Commission, Gnaiger, E., Ahn, B., Alves, M. G., Amati, F., Aral, C., Arandarčikaitė, O., Åsander Frostner, E., Bailey, David M., Bastos Sant'Anna Silva, A. C., Battino, M., Beard, D. A., Newsom, S., Robinson, M. M., Patel, H. H., Buettner, G. R., Pecina, P., Shevchuk, I., Pereira da Silva Grilo da Silva, F., Ben-Shachar, D., Pesta, D., Goodpaster, B. H., Zorzano, Antonio, Petit, P. X., Pichaud, N., Pirkmajer, S., Porter, R. K., Wagner, B. A., Pranger, F., Rohlena, J., Prochownik, E. V., Siewiera, K., Røsland, G. V., Ehinger, J., Rossiter, H. B., Towheed, A., Rybacka-Mossakowska, J., Dias, T., Salvadego, D., Jansen-Dürr, P., Scatena, R., Schartner, M., Scheibye-Knudsen, Morten, Breton, S., Cardoso, L.H.D., Schilling, J. M., Singer, D., Schlattner, U., Brown, R. A., Sobotka, O., Spinazzi, M., Ward, M. L., Brown, G. C., Gonzalo, H., Stankova, P., Labieniec-Watala, M., Stier, A., Stocker, R., Sumbalova, Zuzana, Doerrier, C., Suravajhala, P., Tretter, L., Tanaka, M., Duchen, Michael R., Trivigno, C., Tronstad, K. J., Carvalho, Eugenia, Drahota, Z., Jackson, C. B., Trougakos, I. P., Tyrrell, D. J., Urban, T., Velika, B., Gorr, T. A., Vercesi, A. E., Watala, C., Victor, V. M., Grefte, S., Wei, Y. H., Wieckowski, M. R., O'Gorman, D., Kucera, O., Wohlwend, M., Wolff, J., Wuest, R.C.I., Zaugg, K., Jespersen, N. R., Zaugg, M., Casado, Marta, Calabria, E., Červinková, Zuzana, Chang, S. C., Radenkovic, F., Moisoi, N., Chicco, A. J., Chinopoulos, C., Coen, P. M., Collins, J. L., Lai, N., Crisóstomo, L., Elmer, E., Davis, M. S., Han, J., Endlicher, R., Pak, Y. K., Fell, D. A., Jha, R. K., Ferko, M., Nozickova, K., Ferreira, J.C.B., Scott, G. R., Filipovska, A., Fisar, Z., Fisher, J., García-Rovés, Pablo M., Molina, A.J.A., Garcia-Souza, L. F., Harrison, D. K., Genova, M. L., Kaambre, T., Hellgren, K. T., Hernansanz-Agustín, Pablo, Laner, V., Holland, O., Puurand, M., Hoppel, C. L., Tepp, K., Houstek, J., Hunger, M., Iglesias-Gonzalez, J., Oliveira, P. F., Irving, B. A., Kane, D. A., Iyer, S., Orynbayeva, Z., Kappler, L., Karabatsiakis, A., Montaigne, D., Oliveira, P. J., Schoenfeld, P., Keijer, J., Keppner, G., Komlodi, T., Kopitar-Jerala, N., Reboredo, P., Krako Jakovljevic, N., Larsen, T. S., Kuang, J., Renner-Sattler, K., Lee, H. K., Lemieux, H., Bishop, D., Tandler, B., Lerfall, J., Lucchinetti, E., MacMillan-Crow, L. A., Makrecka-Kuka, M., Shabalina, I. G., Meszaros, A. T., Moore, A. L., Michalak, S., Moreira, B. P., Mracek, T., Distefano, G., Villena, J. A., Muntané, Jordi, Muntean, D. M., Murray, A. J., Nedergaard, J., Tomar, D., Nemec, M., and Palmeira, C. M.

Abstract

As the knowledge base and importance of mitochondrial physiology to human health expand, the necessity for harmonizing nomenclature concerning mitochondrial respiratory states and rates has become increasingly apparent. Clarity of concept and consistency of nomenclature are key trademarks of a research field. These trademarks facilitate effective transdisciplinary communication, education, and ultimately further discovery. Peter Mitchell’s chemiosmotic theory establishes the link between vectorial and scalar energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theory and nomenclature for mitochondrial physiology and bioenergetics. Herein, we follow IUPAC guidelines on general terms of physical chemistry, extended by considerations on open systems and irreversible thermodynamics. We align the nomenclature and symbols of classical bioenergetics with a concept-driven constructive terminology to express the meaning of each quantity clearly and consistently. In this position statement, in the frame of COST Action MitoEAGLE, we endeavour to provide a balanced view on mitochondrial 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 ultimately support the development of databases of mitochondrial respiratory function in species, tissues, and cells.

Published
2018

5. First-in-class inhibitor of HSP110 blocks BCR activation through SYK phosphorylation in diffuse large B-cell lymphoma.

Author

Gibouin VC, Durand M, Boudesco C, Hermetet F, Nozickova K, Chassagne-Clement C, Abdelwahed M, Klener P, Garrido C, and Jego G

Subjects
Humans, Phosphorylation drug effects, Animals, Mice, Pyrimidines pharmacology, Cell Line, Tumor, Tumor Cells, Cultured, Mice, SCID, Quinazolines, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse metabolism, Lymphoma, Large B-Cell, Diffuse pathology, Syk Kinase antagonists & inhibitors, Syk Kinase metabolism, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, HSP110 Heat-Shock Proteins metabolism, Xenograft Model Antitumor Assays
Abstract

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2024
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6. Cyclin dependent kinase 4/6 inhibitor palbociclib synergizes with BCL2 inhibitor venetoclax in experimental models of mantle cell lymphoma without RB1 deletion.

Author

Malarikova D, Jorda R, Kupcova K, Senavova J, Dolnikova A, Pokorna E, Kazantsev D, Nozickova K, Sovilj D, Bellanger C, Chiron D, Andera L, Krystof V, Strnad M, Helman K, Klanova M, Trneny M, Havranek O, and Klener P

Abstract

Background: Mantle cell lymphoma (MCL) is a chronically relapsing malignancy with deregulated cell cycle progression. We analyzed efficacy, mode of action, and predictive markers of susceptibility to palbociclib, an approved CDK 4/6 inhibitor, and its combination with venetoclax, a BCL2 inhibitor., Methods: A panel of nine MCL cell lines were used for in vitro experiments. Four patient derived xenografts (PDX) obtained from patients with chemotherapy and ibrutinib-refractory MCL were used for in vivo proof-of-concept studies. Changes of the mitochondrial membrane potential, energy-metabolic pathways, AKT activity, and pro-apoptotic priming of MCL cells were evaluated by JC-1 staining, Seahorse XF analyser, genetically encoded fluorescent AKT reporter, and BH3 profiling, respectively. MCL clones with gene knockout or transgenic (over)expression of CDKN2A, MYC, CDK4, and RB1 were used to estimate impact of these aberrations on sensitivity to palbociclib, and venetoclax., Results: Co-targeting MCL cells with palbociclib and venetoclax induced cytotoxic synergy in vitro and in vivo. Molecular mechanisms responsible for the observed synthetic lethality comprised palbociclib-mediated downregulation of anti-apoptotic MCL1, increased levels of proapoptotic BIM bound on both BCL2, and BCL-XL and increased pro-apoptotic priming of MCL cells mediated by BCL2-independent mechanisms, predominantly palbociclib-triggered metabolic and mitochondrial stress. Loss of RB1 resulted in palbociclib resistance, while deletion of CDKN2A or overexpression of CDK4, and MYC genes did not change sensitivity to palbociclib., Conclusions: Our data strongly support investigation of the chemotherapy-free palbociclib and venetoclax combination as an innovative treatment strategy for post-ibrutinib MCL patients without RB1 deletion., (© 2024. The Author(s).)

Published
2024
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7. Mechanotransduction-induced glycolysis epigenetically regulates a CXCL1-dominant angiocrine signaling program in liver sinusoidal endothelial cells in vitro and in vivo.

Author

Greuter T, Yaqoob U, Gan C, Jalan-Sakrikar N, Kostallari E, Lu J, Gao J, Sun L, Liu M, Sehrawat TS, Ibrahim SH, Furuta K, Nozickova K, Huang BQ, Gao B, Simons M, Cao S, and Shah VH

Subjects
Actins metabolism, Animals, Chemokine CXCL1 metabolism, Chromatin metabolism, Epigenesis, Genetic, Glycolysis, Histones metabolism, Humans, Liver pathology, Liver Cirrhosis pathology, Mechanotransduction, Cellular, Mice, NF-kappa B metabolism, Endothelial Cells metabolism, Hypertension, Portal metabolism
Abstract

Background & Aims: Liver sinusoidal endothelial cells (LSECs) are ideally situated to sense stiffness and generate angiocrine programs that potentially regulate liver fibrosis and portal hypertension. We explored how specific focal adhesion (FA) proteins parlay LSEC mechanotransduction into stiffness-induced angiocrine signaling in vitro and in vivo., Methods: Primary human and murine LSECs were placed on gels with incremental stiffness (0.2 kPa vs. 32 kPa). Cell response was studied by FA isolation, actin polymerization assay, RNA-sequencing and electron microscopy. Glycolysis was assessed using radioactive tracers. Epigenetic regulation of stiffness-induced genes was analyzed by chromatin-immunoprecipitation (ChIP) analysis of histone activation marks, ChIP sequencing and circularized chromosome conformation capture (4C). Mice with LSEC-selective deletion of glycolytic enzymes (Hk2 fl/fl /Cdh5 cre -ERT2) or treatment with the glycolysis inhibitor 3PO were studied in portal hypertension (partial ligation of the inferior vena cava, pIVCL) and early liver fibrosis (CCl 4 ) models., Results: Glycolytic enzymes, particularly phosphofructokinase 1 isoform P (PFKP), are enriched in isolated FAs from LSECs on gels with incremental stiffness. Stiffness resulted in PFKP recruitment to FAs, which paralleled an increase in glycolysis. Glycolysis was associated with expansion of actin dynamics and was attenuated by inhibition of integrin β1. Inhibition of glycolysis attenuated a stiffness-induced CXCL1-dominant angiocrine program. Mechanistically, glycolysis promoted CXCL1 expression through nuclear pore changes and increases in NF-kB translocation. Biochemically, this CXCL1 expression was mediated through spatial re-organization of nuclear chromatin resulting in formation of super-enhancers, histone acetylation and NF-kB interaction with the CXCL1 promoter. Hk2 fl/fl /Cdh5 cre -ERT2 mice showed attenuated neutrophil infiltration and portal hypertension after pIVCL. 3PO treatment attenuated liver fibrosis in a CCl 4 model., Conclusion: Glycolytic enzymes are involved in stiffness-induced angiocrine signaling in LSECs and represent druggable targets in early liver disease., Lay Summary: Treatment options for liver fibrosis and portal hypertension still represent an unmet need. Herein, we uncovered a novel role for glycolytic enzymes in promoting stiffness-induced angiocrine signaling, which resulted in inflammation, fibrosis and portal hypertension. This work has revealed new targets that could be used in the prevention and treatment of liver fibrosis and portal hypertension., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2022
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