90 results on '"Cuezva, J. M."'
Search Results
2. Margarita Salas, referente indiscutible
- Author
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Ruiz Desviat, Lourdes, Ávila, J., Blanco, L., Cuezva, J. M., Vega, M. de, Mayor Menéndez, F., Mayor Zaragoza, F., UAM. Departamento de Biología Molecular, UAM. Departamento de Bioquímica, and Centro de Biología Molecular Severo Ochoa (CBM)
- Subjects
Severo Ochoa ,Bioquímica y biología molecular ,Margarita Salas ,Científica ,Biología y Biomedicina / Biología - Published
- 2020
3. Coenzyme Q biosynthesis is regulated by RNA-protein interaction: P13-77
- Author
-
Cascajo, M. V., Siendones, E., Abdelmohsen, K., Willers, I. M., Cuezva, J. M., Gorospe, M., and Navas, P.
- Published
- 2012
4. Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356
- Author
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Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Arozena, A. A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., Adhihetty, P. J., Adler, S. G., Agam, G., Agarwal, R., Aghi, M. K., Agnello, M., Agostinis, P., Aguilar, P. V., Aguirre-Ghiso, J., Airoldi, E. M., Ait-Si-Ali, S., Akematsu, T., Akporiaye, E. T., Al-Rubeai, M., Albaiceta, G. M., Albanese, C., Albani, D., Albert, M. L., Aldudo, J., Algül, H., Alirezaei, M., Alloza, I., Almasan, A., Almonte-Beceril, M., Alnemri, E. S., Alonso, C., Altan-Bonnet, N., Altieri, D. C., Alvarez, S., Alvarez-Erviti, L., Alves, S., Amadoro, G., Amano, A., Amantini, C., Ambrosio, S., Amelio, I., Amer, A. O., Amessou, M., Amon, A., An, Z., Anania, F. A., Andersen, S. U., Andley, U. P., Andreadi, C. K., Andrieu-Abadie, N., Anel, A., Ann, D. K., Anoopkumar-Dukie, S., Antonioli, M., Aoki, H., Apostolova, N., Aquila, S., Aquilano, K., Araki, K., Arama, E., Aranda, A., Araya, J., Arcaro, A., Arias, E., Arimoto, H., Ariosa, A. R., Armstrong, J. L., Arnould, T., Arsov, I., Asanuma, K., Askanas, V., Asselin, E., Atarashi, R., Atherton, S. S., Atkin, J. D., Attardi, L. D., Auberger, P., Auburger, G., Aurelian, L., Autelli, R., Avagliano, L., Avantaggiati, M. L., Avrahami, L., Azad, N., Awale, S., Bachetti, T., Backer, J. M., Bae, D. -H., Bae, J. -S., Bae, O. -N., Bae, S. H., Baehrecke, E. H., Baek, S. -H., Baghdiguian, S., Bagniewska-Zadworna, A., Bai, H., Bai, J., Bai, X. -Y., Bailly, Y., Balaji, K. N., Balduini, W., Ballabio, A., Balzan, R., Banerjee, R., Bánhegyi, G., Bao, H., Barbeau, B., Barrachina, M. D., Barreiro, E., Bartel, B., Bartolomé, A., Bassham, D. C., Bassi, M. T., Bast, R. C., J, R., Basu, A., Batista, M. T., Batoko, H., Battino, M., Bauckman, K., Baumgarner, B. L., Bayer, K. U., Beale, R., Beaulieu, J. -F., Beck, G. R., Becker, C., Beckham, J. D., Bédard, P. -A., Bednarski, P. J., Begley, T. J., Behl, C., Behrends, C., Behrens, G. M. N., Behrns, K. E., Bejarano, E., Belaid, A., Belleudi, F., Bénard, G., Berchem, G., Bergamaschi, D., Bergami, M., Berkhout, B., Berliocchi, L., Bernard, A., Bernard, M., Bernassola, F., Bertolotti, A., Bess, A. S., Besteiro, S., Bettuzzi, S., Bhalla, S., Bhattacharyya, S., Bhutia, S. K., Biagosch, C., Bianchi, M. W., Biard-Piechaczyk, M., Billes, V., Bincoletto, C., Bingol, B., Bird, S. W., Bitoun, M., Bjedov, I., Blackstone, C., Blanc, L., Blanco, G. A., Blomhoff, H. K., Boada-Romero, E., Böckler, S., Boes, M., Boesze-Battaglia, K., Boise, L. H., Bolino, A., Boman, A., Bonaldo, P., Bordi, M., Bosch, J., Botana, L. M., Botti, J., Bou, G., Bouché, M., Bouchecareilh, M., Boucher, M. -J., Boulton, M. E., Bouret, S. G., Boya, P., Boyer-Guittaut, M., Bozhkov, P. V., Brady, N., Braga, V. M. M., Brancolini, C., Braus, G. H., Bravo-San-Pedro, J. M., Brennan, L. A., Bresnick, E. H., Brest, P., Bridges, D., Bringer, M. -A., Brini, M., Brito, G. C., Brodin, B., Brookes, P. S., Brown, E. J., Brown, K., Broxmeyer, H. E., Bruhat, A., Brum, P. C., Brumell, J. H., Brunetti-Pierri, N., Bryson-Richardson, R. J., Buch, S., Buchan, A. M., Budak, H., Bulavin, D. V., Bultman, S. J., Bultynck, G., Bumbasirevic, V., Burelle, Y., Burke, R. E., Burmeister, M., Bütikofer, P., Caberlotto, L., Cadwell, K., Cahova, M., Cai, D., Cai, J., Cai, Q., Calatayud, S., Camougrand, N., Campanella, M., Campbell, G. R., Campbell, M., Campello, S., Candau, R., Caniggia, I., Cantoni, L., Cao, L., Caplan, A. B., Caraglia, M., Cardinali, C., Cardoso, S. M., Carew, J. S., Carleton, L. A., Carlin, C. R., Carloni, S., Carlsson, S. R., Carmona-Gutierrez, D., Carneiro, L. A. M., Carnevali, O., Carra, S., Carrier, A., Carroll, B., Casas, C., Casas, J., Cassinelli, G., Castets, P., Castro-Obregon, S., Cavallini, G., Ceccherini, I., Cecconi, F., Cederbaum, A. I., Ceña, V., Cenci, S., Cerella, C., Cervia, D., Cetrullo, S., Chaachouay, H., Chae, H. -J., Chagin, A. S., Chai, C. -Y., Chakrabarti, G., Chamilos, G., Chan, E. Y. W., Chan, M. T. V., Chandra, D., Chandra, P., Chang, C. -P., Chang, R. C. -C., Chang, T. Y., Chatham, J. C., Chatterjee, S., Chauhan, S., Che, Y., Cheetham, M. E., Cheluvappa, R., Chen, C. -J., Chen, G., Chen, G. -C., Chen, H., Chen, J. W., Chen, J. -K., Chen, M., Chen, P., Chen, Q., Chen, S. -D., Chen, S., Chen, S. S. -L., Chen, W., Chen, W. -J., Chen, W. Q., Chen, X., Chen, Y. -H., Chen, Y. -G., Chen, Y., Chen, Y. -J., Chen, Y. -Q., Chen, Z., Cheng, A., Cheng, C. H. K., Cheng, H., Cheong, H., Cherry, S., Chesney, J., Cheung, C. H. A., Chevet, E., Chi, H. C., Chi, S. -G., Chiacchiera, F., Chiang, H. -L., Chiarelli, R., Chiariello, M., Chieppa, M., Chin, L. -S., Chiong, M., Chiu, G. N. C., Cho, D. -H., Cho, S. -G., Cho, W. C., Cho, Y. -Y., Cho, Y. -S., Choi, A. M. K., Choi, E. -J., Choi, E. -K., Choi, J., Choi, M. E., Choi, S. -I., Chou, T. -F., Chouaib, S., Choubey, D., Choubey, V., Chow, K. -C., Chowdhury, K., Chu, C. T., Chuang, T. -H., Chun, T., Chung, H., Chung, T., Chung, Y. -L., Chwae, Y. -J., Cianfanelli, V., Ciarcia, R., Ciechomska, I. A., Ciriolo, M. R., Cirone, M., Claerhout, S., Clague, M. J., Cl� ria, J., Clarke, P. G. H., Clarke, R., Clementi, E., Cleyrat, C., Cnop, M., Coccia, E. M., Cocco, T., Codogno, P., Coers, J., Cohen, E. E. W., Colecchia, D., Coletto, L., Coll, N. S., Colucci-Guyon, E., Comincini, S., Condello, M., Cook, K. L., Coombs, G. H., Cooper, C. D., Cooper, J. M., Coppens, I., Corasaniti, M. T., Corazzari, M., Corbalan, R., Corcelle-Termeau, E., Cordero, M. D., Corral-Ramos, C., Corti, O., Cossarizza, A., Costelli, P., Costes, S., Cotman, S. L., Coto-Montes, A., Cottet, S., Couve, E., Covey, L. R., Cowart, L. A., Cox, J. S., Coxon, F. P., Coyne, C. B., Cragg, M. S., Craven, R. J., Crepaldi, T., Crespo, J. L., Criollo, A., Crippa, V., Cruz, M. T., Cuervo, A. M., Cuezva, J. M., Cui, T., Cutillas, P. R., Czaja, M. J., Czyzyk-Krzeska, M. F., Dagda, R. K., Dahmen, U., Dai, C., Dai, W., Dai, Y., Dalby, K. N., Valle, L. D., Dalmasso, G., D'Amelio, M., Damme, M., Darfeuille-Michaud, A., Dargemont, C., Darley-Usmar, V. M., Dasarathy, S., Dasgupta, B., Dash, S., Dass, C. R., Davey, H. M., Davids, L. M., Dávila, D., Davis, R. J., Dawson, T. M., Dawson, V. L., Daza, P., de Belleroche, J., de Figueiredo, P., de Figueiredo, R. C. B. Q., de la Fuente, J., De Martino, L., De Matteis, A., De Meyer, G. R. Y., De Milito, A., De Santi, M., de Souza, W., De Tata, V., De Zio, D., Debnath, J., Dechant, R., Decuypere, J. -P., Deegan, S., Dehay, B., Del Bello, B., Del Re, D. P., Delage-Mourroux, R., Delbridge, L. M. D., Deldicque, L., Delorme-Axford, E., Deng, Y., Dengjel, J., Denizot, M., Dent, P., Der, C. J., Deretic, V., Derrien, B., Deutsch, E., Devarenne, T. P., Devenish, R. J., Di Bartolomeo, S., Di Daniele, N., Di Domenico, F., Di Nardo, A., Di Paola, S., Di Pietro, A., Di Renzo, L., Di Antonio, A., Díaz-Araya, G., Díaz-Laviada, I., Diaz-Meco, M. T., Diaz-Nido, J., Dickey, C. A., Dickson, R. C., Diederich, M., Digard, P., Dikic, I., Dinesh-Kumar, S. P., Ding, C., Ding, W. -X., Ding, Z., Dini, L., Distler, J. H. W., Diwan, A., Djavaheri-Mergny, M., Dmytruk, K., Dobson, R. C. J., Doetsch, V., Dokladny, K., Dokudovskaya, S., Donadelli, M., Dong, X. C., Dong, X., Dong, Z., Donohue, T. M., Donohue-Jr, T. M., Doran, K. S., D'Orazi, G., Dorn, G. W., Dosenko, V., Dridi, S., Drucker, L., Du, J., L. -L., Du, Du, L., du Toit, A., Dua, P., Duan, L., Duann, P., Dubey, V. K., Duchen, M. R., Duchosal, M. A., Duez, H., Dugail, I., Dumit, V. I., Duncan, M. C., Dunlop, E. A., Dunn, W. A., Dupont, N., Dupuis, L., Durán, R. V., Durcan, T. M., Duvezin-Caubet, S., Duvvuri, U., Eapen, V., Ebrahimi-Fakhari, D., Echard, A., Eckhart, L., Edelstein, C. L., Edinger, A. L., Eichinger, L., Eisenberg, T., Eisenberg-Lerner, A., Eissa, N. T., El-Deiry, W. S., El-Khoury, V., Elazar, Z., Eldar-Finkelman, H., Elliott, C. J. H., Emanuele, E., Emmenegger, U., Engedal, N., Engelbrecht, A. -M., Engelender, S., Enserink, J. M., Erdmann, R., Erenpreisa, J., Eri, R., Eriksen, J. L., Erman, A., Escalante, R., Eskelinen, E. -L., Espert, L., Esteban-Martínez, L., Evans, T. J., Fabri, M., Fabrias, G., Fabrizi, C., Facchiano, A., Færgeman, N. J., Faggioni, A., Fairlie, W. D., Fan, C., Fan, D., Fan, J., Fang, S., Fanto, M., Fanzani, A., Farkas, T., Faure, M., Favier, F. B., Fearnhead, H., Federici, M., Fei, E., Felizardo, T. C., Feng, H., Feng, Y., Ferguson, T. A., Fernández, Á. F., Fernandez-Barrena, M. G., Fernandez-Checa, J. C., Fernández-López, A., Fernandez-Zapico, M. E., Feron, O., Ferraro, E., Ferreira-Halder, C. V., Fesus, L., Feuer, R., Fiesel, F. C., Filippi-Chiela, E. C., Filomeni, G., Fimia, G. M., Fingert, J. H., Finkbeiner, S., Finkel, T., Fiorito, F., Fisher, P. B., Flajolet, M., Flamigni, F., Florey, O., Florio, S., Floto, R. A., Folini, M., Follo, C., Fon, E. A., Fornai, F., Fortunato, F., Fraldi, A., Franco, R., Francois, A., François, A., Frankel, L. B., Fraser, I. D. C., Frey, N., Freyssenet, D. G., Frezza, C., Friedman, S. L., Frigo, D. E., Fu, D., Fuentes, J. M., Fueyo, J., Fujitani, Y., Fujiwara, Y., Fujiya, M., Fukuda, M., Fulda, S., Fusco, C., Gabryel, B., Gaestel, M., Gailly, P., Gajewska, M., Galadari, S., Galili, G., Galindo, I., Galindo, M. F., Galliciotti, G., Galluzzi, L., Galy, V., Gammoh, N., Gandy, S., Ganesan, A. K., Ganesan, S., Ganley, I. G., Gannagé, M., Gao, F. -B., Gao, F., Gao, J. -X., Nannig, L. G., Véscovi, E. G., Garcia-Macía, M., Garcia-Ruiz, C., Garg, A. D., Garg, P. K., Gargini, R., Gassen, N. C., Gatica, D., Gatti, E., Gavard, J., Gavathiotis, E., Ge, L., Ge, P., Ge, S., Gean, P. -W., Gelmetti, V., Genazzani, A. A., Geng, J., Genschik, P., Gerner, L., Gestwicki, J. E., Gewirtz, D. A., Ghavami, S., Ghigo, E., Ghosh, D., Giammarioli, A. M., Giampieri, F., Giampietri, C., Giatromanolaki, A., Gibbings, D. J., Gibellini, L., Gibson, S. B., Ginet, V., Giordano, A., Giorgini, F., Giovannetti, E., Girardin, S. E., Gispert, S., Giuliano, S., Gladson, C. L., Glavic, A., Gleave, M., Godefroy, N., Gogal, R. M., Gokulan, K., Goldman, G. H., Goletti, D., Goligorsky, M. S., Gomes, A. V., Gomes, L. C., Gomez, H., Gomez-Manzano, C., Gómez-Sánchez, R., Gonçalves, D. A. P., Goncu, E., Gong, Q., Gongora, C., Gonzalez, C. B., Gonzalez-Alegre, P., Gonzalez-Cabo, P., González-Polo, R. A., Goping, I. S., Gorbea, C., Gorbunov, N. V., Goring, D. R., Gorman, A. M., Gorski, S. M., Goruppi, S., Goto-Yamada, S., Gotor, C., Gottlieb, R. A., Gozes, I., Gozuacik, D., Graba, Y., Graef, M., Granato, G. E., Grant, G. D., Grant, S., Gravina, G. L., Green, D. R., Greenhough, A., Greenwood, M. T., Grimaldi, B., Gros, F., Grose, C., Groulx, J. -F., Gruber, F., Grumati, P., Grune, T., Guan, J. -L., Guan, K. -L., Guerra, B., Guillen, C., Gulshan, K., Gunst, J., Guo, C., Guo, L., Guo, M., Guo, W., Guo, X. -G., Gust, A. A., Gustafsson, Å. B., Gutierrez, E., Gutierrez, M. G., Gwak, H. -S., Haas, A., Haber, J. E., Hadano, S., Hagedorn, M., Hahn, D. R., Halayko, A. J., Hamacher-Brady, A., Hamada, K., Hamai, A., Hamann, A., Hamasaki, M., Hamer, I., Hamid, Q., Hammond, E. M., Han, F., Han, W., Handa, J. T., Hanover, J. A., Hansen, M., Harada, M., Harhaji-Trajkovic, L., Harper, J. W., Harrath, A. H., Harris, A. L., Harris, J., Hasler, U., Hasselblatt, P., Hasui, K., Hawley, R. G., Hawley, T. S., He, C., C. Y., He, He, F., He, G., R. -R., He, X. -H., He, Y. -W., He, Y. -Y., He, Heath, J. K., Hébert, M. -J., Heinzen, R. A., Helgason, G. V., Hensel, M., Henske, E. P., Her, C., Herman, P. K., Hernández, A., Hernandez, C., Hernández-Tiedra, S., Hetz, C., Hiesinger, P. R., Higaki, K., Hilfiker, S., Hill, B. G., Hill, J. A., Hill, W. D., Hino, K., Hofius, D., Hofman, P., Höglinger, G. U., Höhfeld, J., Holz, M. K., Hong, Y., Hood, D. A., Hoozemans, J. J. M., Hoppe, T., Hsu, C., Hsu, C. -Y., Hsu, L. -C., Hu, D., Hu, G., H. -M., Hu, Hu, H., M. C., Hu, Y. -C., Hu, Z. -W., Hu, Hua, F., Hua, Y., Huang, C., Huang, H. -L., Huang, K. -H., Huang, K. -Y., Huang, S., Huang, W. -P., Huang, Y. -R., Huang, Y., Huber, T. B., Huebbe, P., Huh, W. -K., Hulmi, J. J., Hur, G. M., Hurley, J. H., Husak, Z., Hussain, S. N. A., Hussain, S., Hwang, J. J., Hwang, S., Hwang, T. I. S., Ichihara, A., Imai, Y., Imbriano, C., Inomata, M., Into, T., Iovane, V., Iovanna, J. L., Iozzo, R. V., N. Y., Ip, Irazoqui, J. E., Iribarren, P., Isaka, Y., Isakovic, A. J., Ischiropoulos, H., Isenberg, J. S., Ishaq, M., Ishida, H., Ishii, I., Ishmael, J. E., Isidoro, C., Isobe, K. -I., Isono, E., Issazadeh-Navikas, S., Itahana, K., Itakura, E., Ivanov, A. I., Iyer, A. K. V., Izquierdo, J. M., Izumi, Y., Izzo, V., Jäättelä, M., Jaber, N., Jackson, D. J., Jackson, W. T., Jacob, T. G., Jacques, T. S., Jagannath, C., Jain, A., Jana, N. R., Jang, B. K., Jani, A., Janji, B., Jannig, P. R., Jansson, P. J., Jean, S., Jendrach, M., Jeon, J. -H., Jessen, N., Jeung, E. -B., Jia, K., Jia, L., Jiang, H., Jiang, L., Jiang, T., Jiang, X., Jiang, Y., Jiménez, A., Jin, C., Jin, H., Jin, L., Jin, M., Jin, S., Jinwal, U. K., E. -K., Jo, Johansen, T., Johnson, D. E., Johnson, G. V. W., Johnson, J. D., Jonasch, E., Jones, C., Joosten, L. A. B., Jordan, J., Joseph, A. -M., Joseph, B., Joubert, A. M., Ju, D., Ju, J., Juan, H. -F., Juenemann, K., Juhász, G., Jung, H. S., Jung, J. U., Jung, Y. -K., Jungbluth, H., Justice, M. J., Jutten, B., Kaakoush, N. O., Kaarniranta, K., Kaasik, A., Kabuta, T., Kaeffer, B., Kågedal, K., Kahana, A., Kajimura, S., Kakhlon, O., Kalia, M., Kalvakolanu, D. V., Kamada, Y., Kambas, K., Kaminskyy, V. O., Kampinga, H. H., Kandouz, M., Kang, C., Kang, R., Kang, T. -C., Kanki, T., Kanneganti, T. -D., Kanno, H., Kanthasamy, A. G., Kantorow, M., Kaparakis-Liaskos, M., Kapuy, O., Karantza, V., Karim, M. R., Karmakar, P., Kaser, A., Kaushik, S., Kawula, T., Kaynar, A. M., P. -Y., Ke, Z. -J., Ke, Kehrl, J. H., Keller, K. E., Kemper, J. K., Kenworthy, A. K., Kepp, O., Kern, A., Kesari, S., Kessel, D., Ketteler, R., Kettelhut, I. C., Khambu, B., Khan, M. M., Khandelwal, V. K. M., Khare, S., Kiang, J. G., Kiger, A. A., Kihara, A., Kim, A. L., Kim, C. H., Kim, D. R., Kim, D. -H., Kim, E. K., Kim, H. Y., Kim, H. -R., Kim, J. -S., Kim, J. H., Kim, J. C., Kim, K. W., Kim, M. D., Kim, M. -M., Kim, P. K., Kim, S. W., Kim, S. -Y., Kim, Y. -S., Kim, Y., Kimchi, A., Kimmelman, A. C., Kimura, T., King, J. S., Kirkegaard, K., Kirkin, V., Kirshenbaum, L. A., Kishi, S., Kitajima, Y., Kitamoto, K., Kitaoka, Y., Kitazato, K., Kley, R. A., Klimecki, W. T., Klinkenberg, M., Klucken, J., Knævelsrud, H., Knecht, E., Knuppertz, L., J. -L., Ko, Kobayashi, S., Koch, J. C., Koechlin-Ramonatxo, C., Koenig, U., Koh, Y. H., Köhler, K., Kohlwein, S. D., Koike, M., Komatsu, M., Kominami, E., Kong, D., Kong, H. J., Konstantakou, E. G., Kopp, B. T., Korcsmaros, T., Korhonen, L., Korolchuk, V. I., Koshkina, N. V., Kou, Y., Koukourakis, M. I., Koumenis, C., Kovács, A. L., Kovács, T., Kovacs, W. J., Koya, D., Kraft, C., Krainc, D., Kramer, H., Kravic-Stevovic, T., Krek, W., Kretz-Remy, C., Krick, R., Krishnamurthy, M., Kriston-Vizi, J., Kroemer, G., Kruer, M. C., Kruger, R., Ktistakis, N. T., Kuchitsu, K., Kuhn, C., Kumar, A. P., Kumar, A., Kumar, D., Kumar, R., Kumar, S., Kundu, M., Kung, H. -J., Kuno, A., Kuo, S. -H., Kuret, J., Kurz, T., Kwok, T., Kwon, T. K., Kwon, Y. T., Kyrmizi, I., La Spada, A. R., Lafont, F., Lahm, T., Lakkaraju, A., Lam, T., Lamark, T., Lancel, S., Landowski, T. H., Lane, D. J. R., Lane, J. D., Lanzi, C., Lapaquette, P., Lapierre, L. R., Laporte, J., Laukkarinen, J., Laurie, G. W., Lavandero, S., Lavie, L., Lavoie, M. J., Law, B. Y. K., Law, H. K. -W., Law, K. B., Layfield, R., Lazo, P. A., Le Cam, L., Le Roch, K. G., Le Stunff, H., Leardkamolkarn, V., Lecuit, M., Lee, B. -H., Lee, C. -H., Lee, E. F., Lee, G. M., Lee, H. -J., Lee, H., Lee, J. K., Lee, J., Lee, J. -H., Lee, J. H., Lee, M., Lee, M. -S., Lee, P. J., Lee, S. W., Lee, S. -J., Lee, S. Y., Lee, S. H., Lee, S. S., Lee, S., Lee, Y. -R., Lee, Y. J., Lee, Y. H., Leeuwenburgh, C., Lefort, S., Legouis, R., Lei, J., Lei, Q. -Y., Leib, D. A., Leibowitz, G., Lekli, I., Lemaire, S. D., Lemasters, J. J., Lemberg, M. K., Lemoine, A., Leng, S., Lenz, G., Lenzi, P., Lerman, L. O., Barbato, D. L., Leu, J. I. J., Leung, H. Y., Levine, B., Lewis, P. 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Robin, Higaki, Katsumi, Hilfiker, Sabine, Hill, Bradford G., Hill, Joseph A., Hill, William D., Hino, Keisuke, Hofius, Daniel, Hofman, Paul, Höglinger, Günter U., Höhfeld, Jörg, Holz, Marina K., Hong, Yonggeun, Hood, David A., Hoozemans, Jeroen J.M., Hoppe, Thorsten, Hsu, Chin, Hsu, Chin-Yuan, Hsu, Li-Chung, Hu, Dong, Hu, Guochang, Hu, Hong-Ming, Hu, Hongbo, Hu, Ming Chang, Hu, Yu-Chen, Hu, Zhuo-Wei, Hua, Fang, Hua, Ya, Huang, Canhua, Huang, Huey-Lan, Huang, Kuo-How, Huang, Kuo-Yang, Huang, Shile, Huang, Shiqian, Huang, Wei-Pang, Huang, Yi-Ran, Huang, Yong, Huang, Yunfei, Huber, Tobias B., Huebbe, Patricia, Huh, Won-Ki, Hulmi, Juha J., Hur, Gang Min, Hurley, James H., Husak, Zvenyslava, Hussain, Sabah N.A., Hussain, Salik, Hwang, Jung Jin, Hwang, Seungmin, Hwang, Thomas I.S., Ichihara, Atsuhiro, Imai, Yuzuru, Imbriano, Carol, Inomata, Megumi, Into, Takeshi, Iovane, Valentina, Iovanna, Juan L., Iozzo, Renato V., Ip, Nancy Y., Irazoqui, Javier E., Iribarren, Pablo, Isaka, Yoshitaka, Isakovic, Aleksandra J., Ischiropoulos, Harry, Isenberg, Jeffrey S., Ishaq, Mohammad, Ishida, Hiroyuki, Ishii, Isao, Ishmael, Jane E., Isidoro, Ciro, Isobe, Ken-Ichi, Isono, Erika, Issazadeh-Navikas, Shohreh, Itahana, Koji, Itakura, Eisuke, Ivanov, Andrei I., Iyer, Anand Krishnan V., Izquierdo, José M., Izumi, Yotaro, Izzo, Valentina, Jäättelä, Marja, Jaber, Nadia, Jackson, Daniel John, Jackson, William T., Jacob, Tony George, Jacques, Thomas S., Jagannath, Chinnaswamy, Jain, Ashish, Jana, Nihar Ranjan, Jang, Byoung Kuk, Jani, Alkesh, Janji, Bassam, Jannig, Paulo Roberto, Jansson, Patric J., Jean, Steve, Jendrach, Marina, Jeon, Ju-Hong, Jessen, Niel, Jeung, Eui-Bae, Jia, Kailiang, Jia, Lijun, Jiang, Hong, Jiang, Hongchi, Jiang, Liwen, Jiang, Teng, Jiang, Xiaoyan, Jiang, Xuejun, Jiang, Ying, Jiang, Yongjun, Jiménez, Alberto, Jin, Cheng, Jin, Hongchuan, Jin, Lei, Jin, Meiyan, Jin, Shengkan, Jinwal, Umesh Kumar, Jo, Eun-Kyeong, Johansen, Terje, Johnson, Daniel E., Johnson, Gail V.W., Johnson, James D., Jonasch, Eric, Jones, Chri, Joosten, Leo A.B., Jordan, Joaquin, Joseph, Anna-Maria, Joseph, Bertrand, Joubert, Annie M., Ju, Dianwen, Ju, Jingfang, Juan, Hsueh-Fen, Juenemann, Katrin, Juhász, Gábor, Jung, Hye Seung, Jung, Jae U., Jung, Yong-Keun, Jungbluth, Heinz, Justice, Matthew J., Jutten, Barry, Kaakoush, Nadeem O., Kaarniranta, Kai, Kaasik, Allen, Kabuta, Tomohiro, Kaeffer, Bertrand, Kågedal, Katarina, Kahana, Alon, Kajimura, Shingo, Kakhlon, Or, Kalia, Manjula, Kalvakolanu, Dhan V., Kamada, Yoshiaki, Kambas, Konstantino, Kaminskyy, Vitaliy O., Kampinga, Harm H., Kandouz, Mustapha, Kang, Chanhee, Kang, Rui, Kang, Tae-Cheon, Kanki, Tomotake, Kanneganti, Thirumala-Devi, Kanno, Haruo, Kanthasamy, Anumantha G., Kantorow, Marc, Kaparakis-Liaskos, Maria, Kapuy, Orsolya, Karantza, Vassiliki, Karim, Md Razaul, Karmakar, Parimal, Kaser, Arthur, Kaushik, Susmita, Kawula, Thoma, Kaynar, A. Murat, Ke, Po-Yuan, Ke, Zun-Ji, Kehrl, John H., Keller, Kate E., Kemper, Jongsook Kim, Kenworthy, Anne K., Kepp, Oliver, Kern, Andrea, Kesari, Santosh, Kessel, David, Ketteler, Robin, Kettelhut, Isis do Carmo, Khambu, Bilon, Khan, Muzamil Majid, Khandelwal, Vinoth K.M., Khare, Sangeeta, Kiang, Juliann G., Kiger, Amy A., Kihara, Akio, Kim, Arianna L., Kim, Cheol Hyeon, Kim, Deok Ryong, Kim, Do-Hyung, Kim, Eung Kweon, Kim, Hye Young, Kim, Hyung-Ryong, Kim, Jae-Sung, Kim, Jeong Hun, Kim, Jin Cheon, Kim, Jin Hyoung, Kim, Kwang Woon, Kim, Michael D., Kim, Moon-Moo, Kim, Peter K., Kim, Seong Who, Kim, Soo-Youl, Kim, Yong-Sun, Kim, Yonghyun, Kimchi, Adi, Kimmelman, Alec C., Kimura, Tomonori, King, Jason S., Kirkegaard, Karla, Kirkin, Vladimir, Kirshenbaum, Lorrie A., Kishi, Shuji, Kitajima, Yasuo, Kitamoto, Katsuhiko, Kitaoka, Yasushi, Kitazato, Kaio, Kley, Rudolf A., Klimecki, Walter T., Klinkenberg, Michael, Klucken, Jochen, Knævelsrud, Helene, Knecht, Erwin, Knuppertz, Laura, Ko, Jiunn-Liang, Kobayashi, Satoru, Koch, Jan C., Koechlin-Ramonatxo, Christelle, Koenig, Ulrich, Koh, Young Ho, Köhler, Katja, Kohlwein, Sepp D., Koike, Masato, Komatsu, Masaaki, Kominami, Eiki, Kong, Dexin, Kong, Hee Jeong, Konstantakou, Eumorphia G., Kopp, Benjamin T., Korcsmaros, Tama, Korhonen, Laura, Korolchuk, Viktor I., Koshkina, Nadya V., Kou, Yanjun, Koukourakis, Michael I., Koumenis, Constantino, Kovács, Attila L., Kovács, Tibor, Kovacs, Werner J., Koya, Daisuke, Kraft, Claudine, Krainc, Dimitri, Kramer, Helmut, Kravic-Stevovic, Tamara, Krek, Wilhelm, Kretz-Remy, Carole, Krick, Roswitha, Krishnamurthy, Malathi, Kriston-Vizi, Jano, Kroemer, Guido, Kruer, Michael C., Kruger, Rejko, Ktistakis, Nicholas T., Kuchitsu, Kazuyuki, Kuhn, Christian, Kumar, Addanki Pratap, Kumar, Anuj, Kumar, Ashok, Kumar, Deepak, Kumar, Dhiraj, Kumar, Rakesh, Kumar, Sharad, Kundu, Mondira, Kung, Hsing-Jien, Kuno, Atsushi, Kuo, Sheng-Han, Kuret, Jeff, Kurz, Tino, Kwok, Terry, Kwon, Taeg Kyu, Kwon, Yong Tae, Kyrmizi, Irene, La Spada, Albert R., Lafont, Frank, Lahm, Tim, Lakkaraju, Aparna, Lam, Truong, Lamark, Trond, Lancel, Steve, Landowski, Terry H., Lane, Darius J.R., Lane, Jon D., Lanzi, Cinzia, Lapaquette, Pierre, Lapierre, Louis R., Laporte, Jocelyn, Laukkarinen, Johanna, Laurie, Gordon W., Lavandero, Sergio, Lavie, Lena, Lavoie, Matthew J., Law, Betty Yuen Kwan, Law, Helen Ka-Wai, Law, Kelsey B., Layfield, Robert, Lazo, Pedro A., Le Cam, Laurent, Le Roch, Karine G., Le Stunff, Hervé, Leardkamolkarn, Vijittra, Lecuit, Marc, Lee, Byung-Hoon, Lee, Che-Hsin, Lee, Erinna F., Lee, Gyun Min, Lee, He-Jin, Lee, Hsinyu, Lee, Jae Keun, Lee, Jongdae, Lee, Ju-Hyun, Lee, Jun Hee, Lee, Michael, Lee, Myung-Shik, Lee, Patty J., Lee, Sam W., Lee, Seung-Jae, Lee, Shiow-Ju, Lee, Stella Y., Lee, Sug Hyung, Lee, Sung Sik, Lee, Sung-Joon, Lee, Sunhee, Lee, Ying-Ray, Lee, Yong J., Lee, Young H., Leeuwenburgh, Christiaan, Lefort, Sylvain, Legouis, Renaud, Lei, Jinzhi, Lei, Qun-Ying, Leib, David A., Leibowitz, Gil, Lekli, Istvan, Lemaire, Stéphane D., Lemasters, John J., Lemberg, Marius K., Lemoine, Antoinette, Leng, Shuilong, Lenz, Guido, Lenzi, Paola, Lerman, Lilach O., Barbato, Daniele Lettieri, Leu, Julia I. 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Sue, Menna-Barreto, Rubem F.S., Menon, Manoj B., Meraz-Ríos, Marco A., Merla, Giuseppe, Merlini, Luciano, Merlot, Angelica M., Meryk, Andrea, Meschini, Stefania, Meyer, Joel N., Mi, Man-Tian, Miao, Chao-Yu, Micale, Lucia, Michaeli, Simon, Michiels, Carine, Migliaccio, Anna Rita, Mihailidou, Anastasia Susie, Mijaljica, Dalibor, Mikoshiba, Katsuhiko, Milan, Enrico, Miller-Fleming, Leonor, Mills, Gordon B., Mills, Ian G., Minakaki, Georgia, Minassian, Berge A., Ming, Xiu-Fen, Minibayeva, Farida, Minina, Elena A., Mintern, Justine D., Minucci, Saverio, Miranda-Vizuete, Antonio, Mitchell, Claire H., Miyamoto, Shigeki, Miyazawa, Keisuke, Mizushima, Noboru, Mnich, Katarzyna, Mograbi, Baharia, Mohseni, Simin, Moita, Luis Ferreira, Molinari, Marco, Molinari, Maurizio, Møller, Andreas Buch, Mollereau, Bertrand, Mollinedo, Faustino, Mongillo, Marco, Monick, Martha M., Montagnaro, Serena, Montell, Craig, Moore, Darren J., Moore, Michael N., Mora-Rodriguez, Rodrigo, Moreira, Paula I., Morel, Etienne, Morelli, Maria Beatrice, Moreno, Sandra, Morgan, Michael J., Moris, Arnaud, Moriyasu, Yuji, Morrison, Janna L., Morrison, Lynda A., Morselli, Eugenia, Moscat, Jorge, Moseley, Pope L., Mostowy, Serge, Motori, Elisa, Mottet, Deni, Mottram, Jeremy C., Moussa, Charbel E.-H., Mpakou, Vassiliki E., Mukhtar, Hasan, Levy, Jean M. Mulcahy, Muller, Sylviane, Muñoz-Moreno, Raquel, Muñoz-Pinedo, Cristina, Münz, Christian, Murphy, Maureen E., Murray, James T., Murthy, Aditya, Mysorekar, Indira U., Nabi, Ivan R., Nabissi, Massimo, Nader, Gustavo A., Nagahara, Yukitoshi, Nagai, Yoshitaka, Nagata, Kazuhiro, Nagelkerke, Anika, Nagy, Péter, Naidu, Samisubbu R., Nair, Sreejayan, Nakano, Hiroyasu, Nakatogawa, Hitoshi, Nanjundan, Meera, Napolitano, Gennaro, Naqvi, Naweed I., Nardacci, Roberta, Narendra, Derek P., Narita, Masashi, Nascimbeni, Anna Chiara, Natarajan, Ramesh, Navegantes, Luiz C., Nawrocki, Steffan T., Nazarko, Taras Y., Nazarko, Volodymyr Y., Neill, Thoma, Neri, Luca M., Netea, Mihai G., Netea-Maier, Romana T., Neves, Bruno M., Ney, Paul A., Nezis, Ioannis P., Nguyen, Hang T.T., Nguyen, Huu Phuc, Nicot, Anne-Sophie, Nilsen, Hilde, Nilsson, Per, Nishimura, Mikio, Nishino, Ichizo, Niso-Santano, Mireia, Niu, Hua, Nixon, Ralph A., Njar, Vincent C.O., Noda, Takeshi, Noegel, Angelika A., Nolte, Elsie Magdalena, Norberg, Erik, Norga, Koenraad K., Noureini, Sakineh Kazemi, Notomi, Shoji, Notterpek, Lucia, Nowikovsky, Karin, Nukina, Nobuyuki, Nürnberger, Thorsten, O'donnell, Valerie B., O'donovan, Tracey, O'dwyer, Peter J., Oehme, Ina, Oeste, Clara L., Ogawa, Michinaga, Ogretmen, Besim, Ogura, Yuji, Oh, Young J., Ohmuraya, Masaki, Ohshima, Takayuki, Ojha, Rani, Okamoto, Koji, Okazaki, Toshiro, Oliver, F. Javier, Ollinger, Karin, Olsson, Stefan, Orban, Daniel P., Ordonez, Paulina, Orhon, Idil, Orosz, Laszlo, O'rourke, Eyleen J., Orozco, Helena, Ortega, Angel L., Ortona, Elena, Osellame, Laura D., Oshima, Junko, Oshima, Shigeru, Osiewacz, Heinz D., Otomo, Takanobu, Otsu, Kinya, Ou, Jing-Hsiung Jame, Outeiro, Tiago F., Ouyang, Dong-Yun, Ouyang, Hongjiao, Overholtzer, Michael, Ozbun, Michelle A., Ozdinler, P. Hande, Ozpolat, Bulent, Pacelli, Consiglia, Paganetti, Paolo, Page, Guyléne, Pages, Gille, Pagnini, Ugo, Pajak, Beata, Pak, Stephen C., Pakos-Zebrucka, Karolina, Pakpour, Nazzy, Palková, Zdena, Palladino, Francesca, Pallauf, Kathrin, Pallet, Nicola, Palmieri, Marta, Paludan, Søren R., Palumbo, Camilla, Palumbo, Silvia, Pampliega, Olatz, Pan, Hongming, Pan, Wei, Panaretakis, Theochari, Pandey, Aseem, Pantazopoulou, Areti, Papackova, Zuzana, Papademetrio, Daniela L., Papassideri, Issidora, Papini, Alessio, Parajuli, Nirmala, Pardo, Julian, Parekh, Vrajesh V., Parenti, Giancarlo, Park, Jong-In, Park, Junsoo, Park, Ohkmae K., Parker, Roy, Parlato, Rosanna, Parys, Jan B., Parzych, Katherine R., Pasquet, Jean-Max, Pasquier, Benoit, Pasumarthi, Kishore B.S., Patschan, Daniel, Pattingre, Sophie, Pattison, Scott, Pause, Arnim, Pavenstädt, Hermann, Pavone, Flaminia, Pedrozo, Zully, Peña, Fernando J., Peñalva, Miguel A., Pende, Mario, Peng, Jianxin, Penna, Fabio, Penninger, Josef M., Pensalfini, Anna, Pepe, Salvatore, Pereira, Gustavo J.S., Pereira, Paulo C., de la Cruz, Verónica Pérez, Pérez-Pérez, María Esther, Pérez-Rodríguez, Diego, Pérez-Sala, Dolore, Perier, Celine, Perl, Andra, Perlmutter, David H., Perrotta, Ida, Pervaiz, Shazib, Pesonen, Maija, Pessin, Jeffrey E., Peters, Godefridus J., Petersen, Morten, Petrache, Irina, Petrof, Basil J., Petrovski, Goran, Phang, James M., Piacentini, Mauro, Pierdominici, Marina, Pierre, Philippe, Pierrefite-Carle, Valérie, Pietrocola, Federico, Pimentel-Muiños, Felipe X., Pinar, Mario, Pineda, Benjamin, Pinkas-Kramarski, Ronit, Pinti, Marcello, Pinton, Paolo, Piperdi, Bilal, Piret, James M., Platanias, Leonidas C., Platta, Harald W., Plowey, Edward D., Pöggeler, Stefanie, Poirot, Marc, Polčic, Peter, Poletti, Angelo, Poon, Audrey H., Popelka, Hana, Popova, Blagovesta, Poprawa, Izabela, Poulose, Shibu M., Poulton, Joanna, Powers, Scott K., Powers, Ted, Pozuelo-Rubio, Mercede, Prak, Krisna, Prange, Reinhild, Prescott, Mark, Priault, Muriel, Prince, Sharon, Proia, Richard L., Proikas-Cezanne, Tassula, Prokisch, Holger, Promponas, Vasilis J., Przyklenk, Karin, Puertollano, Rosa, Pugazhenthi, Subbiah, Puglielli, Luigi, Pujol, Aurora, Puyal, Julien, Pyeon, Dohun, Qi, Xin, Qian, Wen-Bin, Qin, Zheng-Hong, Qiu, Yu, Qu, Ziwei, Quadrilatero, Joe, Quinn, Frederick, Raben, Nina, Rabinowich, Hannah, Radogna, Flavia, Ragusa, Michael J., Rahmani, Mohamed, Raina, Komal, Ramanadham, Sasanka, Ramesh, Rajagopal, Rami, Abdelhaq, Randall-Demllo, Sarron, Randow, Felix, Rao, Hai, Rao, V. Ashutosh, Rasmussen, Blake B., Rasse, Tobias M., Ratovitski, Edward A., Rautou, Pierre-Emmanuel, Ray, Swapan K., Razani, Babak, Reed, Bruce H., Reggiori, Fulvio, Rehm, Marku, Reichert, Andreas S., Rein, Theo, Reiner, David J., Reits, Eric, Ren, Jun, Ren, Xingcong, Renna, Maurizio, Reusch, Jane E.B., Revuelta, Jose L., Reyes, Leticia, Rezaie, Alireza R., Richards, Robert I., Richardson, Des R., Richetta, Clémence, Riehle, Michael A., Rihn, Bertrand H., Rikihisa, Yasuko, Riley, Brigit E., Rimbach, Gerald, Rippo, Maria Rita, Ritis, Konstantino, Rizzi, Federica, Rizzo, Elizete, Roach, Peter J., Robbins, Jeffrey, Roberge, Michel, Roca, Gabriela, Roccheri, Maria Carmela, Rocha, Sonia, Rodrigues, Cecilia M.P., Rodríguez, Clara I., de Cordoba, Santiago Rodriguez, Rodriguez-Muela, Natalia, Roelofs, Jeroen, Rogov, Vladimir V., Rohn, Troy T., Rohrer, Bärbel, Romanelli, Davide, Romani, Luigina, Romano, Patricia Silvia, Roncero, M. Isabel G., Rosa, Jose Lui, Rosello, Alicia, Rosen, Kirill V., Rosenstiel, Philip, Rost-Roszkowska, Magdalena, Roth, Kevin A., Roué, Gael, Rouis, Mustapha, Rouschop, Kasper M., Ruan, Daniel T., Ruano, Diego, Rubinsztein, David C., Rucker, Edmund B., Rudich, Assaf, Rudolf, Emil, Rudolf, Ruediger, Ruegg, Markus A., Ruiz-Roldan, Carmen, Ruparelia, Avnika Ashok, Rusmini, Paola, Russ, David W., Russo, Gian Luigi, Russo, Giuseppe, Russo, Rossella, Rusten, Tor Erik, Ryabovol, Victoria, Ryan, Kevin M., Ryter, Stefan W., Sabatini, David M., Sacher, Michael, Sachse, Carsten, Sack, Michael N., Sadoshima, Junichi, Saftig, Paul, Sagi-Eisenberg, Ronit, Sahni, Sumit, Saikumar, Pothana, Saito, Tsunenori, Saitoh, Tatsuya, Sakakura, Koichi, Sakoh-Nakatogawa, Machiko, Sakuraba, Yasuhito, Salazar-Roa, María, Salomoni, Paolo, Saluja, Ashok K., Salvaterra, Paul M., Salvioli, Rosa, Samali, Afshin, Sanchez, Anthony M.J., Sánchez-Alcázar, José A., Sanchez-Prieto, Ricardo, Sandri, Marco, Sanjuan, Miguel A., Santaguida, Stefano, Santambrogio, Laura, Santoni, Giorgio, Dos Santos, Claudia Nune, Saran, Shweta, Sardiello, Marco, Sargent, Graeme, Sarkar, Pallabi, Sarkar, Sovan, Sarrias, Maria Rosa, Sarwal, Minnie M., Sasakawa, Chihiro, Sasaki, Motoko, Sass, Miklo, Sato, Ken, Sato, Miyuki, Satriano, Joseph, Savaraj, Niramol, Saveljeva, Svetlana, Schaefer, Liliana, Schaible, Ulrich E., Scharl, Michael, Schatzl, Hermann M., Schekman, Randy, Scheper, Wiep, Schiavi, Alfonso, Schipper, Hyman M., Schmeisser, Hana, Schmidt, Jen, Schmitz, Ingo, Schneider, Bianca E., Schneider, E. Marion, Schneider, Jaime L., Schon, Eric A., Schönenberger, Miriam J., Schönthal, Axel H., Schorderet, Daniel F., Schröder, Bernd, Schuck, Sebastian, Schulze, Ryan J., Schwarten, Melanie, Schwarz, Thomas L., Sciarretta, Sebastiano, Scotto, Kathleen, Scovassi, A. Ivana, Screaton, Robert A., Screen, Mark, Seca, Hugo, Sedej, Simon, Segatori, Laura, Segev, Nava, Seglen, Per O., Seguí-Simarro, Jose M., Segura-Aguilar, Juan, Seiliez, Iban, Seki, Ekihiro, Sell, Christian, Semenkovich, Clay F., Semenza, Gregg L., Sen, Utpal, Serra, Andreas L., Serrano-Puebla, Ana, Sesaki, Hiromi, Setoguchi, Takao, Settembre, Carmine, Shacka, John J., Shajahan-Haq, Ayesha N., Shapiro, Irving M., Sharma, Shweta, She, Hua, Shen, C.-K. Jame, Shen, Chiung-Chyi, Shen, Han-Ming, Shen, Sanbing, Shen, Weili, Sheng, Rui, Sheng, Xianyong, Sheng, Zu-Hang, Shepherd, Trevor G., Shi, Junyan, Shi, Qiang, Shi, Qinghua, Shi, Yuguang, Shibutani, Shusaku, Shibuya, Kenichi, Shidoji, Yoshihiro, Shieh, Jeng-Jer, Shih, Chwen-Ming, Shimada, Yohta, Shimizu, Shigeomi, Shin, Dong Wook, Shinohara, Mari L., Shintani, Michiko, Shintani, Takahiro, Shioi, Tetsuo, Shirabe, Ken, Shiri-Sverdlov, Ronit, Shirihai, Orian, Shore, Gordon C., Shu, Chih-Wen, Shukla, Deepak, Sibirny, Andriy A., Sica, Valentina, Sigurdson, Christina J., Sigurdsson, Einar M., Sijwali, Puran Singh, Sikorska, Beata, Silveira, Wilian A., Silvente-Poirot, Sandrine, Silverman, Gary A., Simak, Jan, Simmet, Thoma, Simon, Anna Katharina, Simon, Hans-Uwe, Simone, Cristiano, Simons, Matia, Simonsen, Anne, Singh, Rajat, Singh, Shivendra V., Singh, Shrawan K., Sinha, Debasish, Sinha, Sangita, Sinicrope, Frank A., Sirko, Agnieszka, Sirohi, Kapil, Sishi, Balindiwe J.N., Sittler, Annie, Siu, Parco M., Sivridis, Efthimio, Skwarska, Anna, Slack, Ruth, Slaninová, Iva, Slavov, Nikolai, Smaili, Soraya S., Smalley, Keiran S.M., Smith, Duncan R., Soenen, Stefaan J., Soleimanpour, Scott A., Solhaug, Anita, Somasundaram, Kumaravel, Son, Jin H., Sonawane, Avinash, Song, Chunjuan, Song, Fuyong, Song, Hyun Kyu, Song, Ju-Xian, Song, Wei, Soo, Kai Y., Sood, Anil K., Soong, Tuck Wah, Soontornniyomkij, Virawudh, Sorice, Maurizio, Sotgia, Federica, Soto-Pantoja, David R., Sotthibundhu, Areechun, Sousa, Maria João, Spaink, Herman P., Span, Paul N., Spang, Anne, Sparks, Janet D., Speck, Peter G., Spector, Stephen A., Spies, Claudia D., Springer, Wolfdieter, Clair, Daret St, Stacchiotti, Alessandra, Staels, Bart, Stang, Michael T., Starczynowski, Daniel T., Starokadomskyy, Petro, Steegborn, Clemen, Steele, John W., Stefanis, Leonida, Steffan, Joan, Stellrecht, Christine M., Stenmark, Harald, Stepkowski, Tomasz M., Stern, Stęphan T., Stevens, Craig, Stockwell, Brent R., Stoka, Veronika, Storchova, Zuzana, Stork, Björn, Stratoulias, Vassili, Stravopodis, Dimitrios J., Strnad, Pavel, Strohecker, Anne Marie, Ström, Anna-Lena, Stromhaug, Per, Stulik, Jiri, Su, Yu-Xiong, Su, Zhaoliang, Subauste, Carlos S., Subramaniam, Srinivasa, Sue, Carolyn M., Suh, Sang Won, Sui, Xinbing, Sukseree, Supawadee, Sulzer, David, Sun, Fang-Lin, Sun, Jiaren, Sun, Jun, Sun, Shi-Yong, Sun, Yang, Sun, Yi, Sun, Yingjie, Sundaramoorthy, Vinod, Sung, Joseph, Suzuki, Hidekazu, Suzuki, Kuninori, Suzuki, Naoki, Suzuki, Tadashi, Suzuki, Yuichiro J., Swanson, Michele S., Swanton, Charle, Swärd, Karl, Swarup, Ghanshyam, Sweeney, Sean T., Sylvester, Paul W., Szatmari, Zsuzsanna, Szegezdi, Eva, Szlosarek, Peter W., Taegtmeyer, Heinrich, Tafani, Marco, Taillebourg, Emmanuel, Tait, Stephen W.G., Takacs-Vellai, Krisztina, Takahashi, Yoshinori, Takáts, Szabolc, Takemura, Genzou, Takigawa, Nagio, Talbot, Nicholas J., Tamagno, Elena, Tamburini, Jerome, Tan, Cai-Ping, Tan, Lan, Tan, Mei Lan, Tan, Ming, Tan, Yee-Joo, Tanaka, Keiji, Tanaka, Masaki, Tang, Daolin, Tang, Dingzhong, Tang, Guomei, Tanida, Isei, Tanji, Kunikazu, Tannous, Bakhos A., Tapia, Jose A., Tasset-Cuevas, Inmaculada, Tatar, Marc, Tavassoly, Iman, Tavernarakis, Nektario, Taylor, Allen, Taylor, Graham S., Taylor, Gregory A., Taylor, J. Paul, Taylor, Mark J., Tchetina, Elena V., Tee, Andrew R., Teixeira-Clerc, Fatima, Telang, Sucheta, Tencomnao, Tewin, Teng, Ba-Bie, Teng, Ru-Jeng, Terro, Faraj, Tettamanti, Gianluca, Theiss, Arianne L., Theron, Anne E., Thomas, Kelly Jean, Thomé, Marcos P., Thomes, Paul G., Thorburn, Andrew, Thorner, Jeremy, Thum, Thoma, Thumm, Michael, Thurston, Teresa L.M., Tian, Ling, Till, Andrea, Ting, Jenny Pan-Yun, Ting, Jenny Pan Yun, Titorenko, Vladimir I., Toker, Lilach, Toldo, Stefano, Tooze, Sharon A., Topisirovic, Ivan, Torgersen, Maria Lyngaa, Torosantucci, Liliana, Torriglia, Alicia, Torrisi, Maria Rosaria, Tournier, Cathy, Towns, Roberto, Trajkovic, Vladimir, Travassos, Leonardo H., Triola, Gemma, Tripathi, Durga Nand, Trisciuoglio, Daniela, Troncoso, Rodrigo, Trougakos, Ioannis P., Truttmann, Anita C., Tsai, Kuen-Jer, Tschan, Mario P., Tseng, Yi-Hsin, Tsukuba, Takayuki, Tsung, Allan, Tsvetkov, Andrey S., Tu, Shuiping, Tuan, Hsing-Yu, Tucci, Marco, Tumbarello, David A., Turk, Bori, Turk, Vito, Turner, Robin F.B., Tveita, Anders A., Tyagi, Suresh C., Ubukata, Makoto, Uchiyama, Yasuo, Udelnow, Andrej, Ueno, Takashi, Umekawa, Midori, Umemiya-Shirafuji, Rika, Underwood, Benjamin R., Ungermann, Christian, Ureshino, Rodrigo P., Ushioda, Ryo, Uversky, Vladimir N., Uzcátegui, Néstor L., Vaccari, Thoma, Vaccaro, Maria I., Váchová, Libuše, Vakifahmetoglu-Norberg, Helin, Valdor, Rut, Valente, Enza Maria, Vallette, Francoi, Valverde, Angela M., Van den Berghe, Greet, Van Den Bosch, Ludo, van den Brink, Gijs R., van der Goot, F. Gisou, van der Klei, Ida J., van der Laan, Luc J.W., van Doorn, Wouter G., van Egmond, Marjolein, van Golen, Kenneth L., Van Kaer, Luc, Campagne, Menno van Lookeren, Vandenabeele, Peter, Vandenberghe, Wim, Vanhorebeek, Ilse, Varela-Nieto, Isabel, Vasconcelos, M. Helena, Vasko, Radovan, Vavvas, Demetrios G., Vega-Naredo, Ignacio, Velasco, Guillermo, Velentzas, Athanassios D., Velentzas, Panagiotis D., Vellai, Tibor, Vellenga, Edo, Vendelbo, Mikkel Holm, Venkatachalam, Kartik, Ventura, Natascia, Ventura, Salvador, Veras, Patrícia S.T., Verdier, Mireille, Vertessy, Beata G., Viale, Andrea, Vidal, Michel, Vieira, Helena L.A., Vierstra, Richard D., Vigneswaran, Nadarajah, Vij, Neeraj, Vila, Miquel, Villar, Margarita, Villar, Victor H., Villarroya, Joan, Vindis, Cécile, Viola, Giampietro, Viscomi, Maria Teresa, Vitale, Giovanni, Vogl, Dan T., Voitsekhovskaja, Olga V., von Haefen, Clarissa, von Schwarzenberg, Karin, Voth, Daniel E., Vouret-Craviari, Valérie, Vuori, Kristina, Vyas, Jatin M., Waeber, Christian, Walker, Cheryl Lyn, Walker, Mark J., Walter, Jochen, Wan, Lei, Wan, Xiangbo, Wang, Bo, Wang, Caihong, Wang, Chao-Yung, Wang, Chengshu, Wang, Chenran, Wang, Chuangui, Wang, Dong, Wang, Fen, Wang, Fuxin, Wang, Guanghui, Wang, Hai-Jie, Wang, Haichao, Wang, Hong-Gang, Wang, Hongmin, Wang, Horng-Dar, Wang, Jing, Wang, Junjun, Wang, Mei, Wang, Mei-Qing, Wang, Pei-Yu, Wang, Peng, Wang, Richard C., Wang, Shuo, Wang, Ting-Fang, Wang, Xian, Wang, Xiao-Jia, Wang, Xiao-Wei, Wang, Xin, Wang, Xuejun, Wang, Yan, Wang, Yanming, Wang, Ying, Wang, Ying-Jan, Wang, Yipeng, Wang, Yu, Wang, Yu Tian, Wang, Yuqing, Wang, Zhi-Nong, Wappner, Pablo, Ward, Carl, Ward, Diane McVey, Warnes, Gary, Watada, Hirotaka, Watanabe, Yoshihisa, Watase, Kei, Weaver, Timothy E., Weekes, Colin D., Wei, Jiwu, Weide, Thoma, Weihl, Conrad C., Weindl, Günther, Weis, Simone Nardin, Wen, Longping, Wen, Xin, Wen, Yunfei, Westermann, Benedikt, Weyand, Cornelia M., White, Anthony R., White, Eileen, Whitton, J. Lindsay, Whitworth, Alexander J., Wiels, Joëlle, Wild, Franziska, Wildenberg, Manon E., Wileman, Tom, Wilkinson, Deepti Sriniva, Wilkinson, Simon, Willbold, Dieter, Williams, Chri, Williams, Katherine, Williamson, Peter R., Winklhofer, Konstanze F., Witkin, Steven S., Wohlgemuth, Stephanie E., Wollert, Thoma, Wolvetang, Ernst J., Wong, Esther, Wong, G. William, Wong, Richard W., Wong, Vincent Kam Wai, Woodcock, Elizabeth A., Wright, Karen L., Wu, Chunlai, Wu, Defeng, Wu, Gen Sheng, Wu, Jian, Wu, Junfang, Wu, Mian, Wu, Min, Wu, Shengzhou, Wu, William K.K., Wu, Yaohua, Wu, Zhenlong, Xavier, Cristina P.R., Xavier, Ramnik J., Xia, Gui-Xian, Xia, Tian, Xia, Weiliang, Xia, Yong, Xiao, Hengyi, Xiao, Jian, Xiao, Shi, Xiao, Wuhan, Xie, Chuan-Ming, Xie, Zhiping, Xie, Zhonglin, Xilouri, Maria, Xiong, Yuyan, Xu, Chuanshan, Xu, Congfeng, Xu, Feng, Xu, Haoxing, Xu, Hongwei, Xu, Jian, Xu, Jianzhen, Xu, Jinxian, Xu, Liang, Xu, Xiaolei, Xu, Yangqing, Xu, Ye, Xu, Zhi-Xiang, Xu, Ziheng, Xue, Yu, Yamada, Takahiro, Yamamoto, Ai, Yamanaka, Koji, Yamashina, Shunhei, Yamashiro, Shigeko, Yan, Bing, Yan, Bo, Yan, Xianghua, Yan, Zhen, Yanagi, Yasuo, Yang, Dun-Sheng, Yang, Jin-Ming, Yang, Liu, Yang, Minghua, Yang, Pei-Ming, Yang, Peixin, Yang, Qian, Yang, Wannian, Yang, Wei Yuan, Yang, Xuesong, Yang, Yi, Yang, Ying, Yang, Zhifen, Yang, Zhihong, Yao, Meng-Chao, Yao, Pamela J., Yao, Xiaofeng, Yao, Zhenyu, Yao, Zhiyuan, Yasui, Linda S., Ye, Mingxiang, Yedvobnick, Barry, Yeganeh, Behzad, Yeh, Elizabeth S., Yeyati, Patricia L., Yi, Fan, Yi, Long, Yin, Xiao-Ming, Yip, Calvin K., Yoo, Yeong-Min, Yoo, Young Hyun, Yoon, Seung-Yong, Yoshida, Ken-Ichi, Yoshimori, Tamotsu, Young, Ken H., Yu, Huixin, Yu, Jane J., Yu, Jin-Tai, Yu, Jun, Yu, Li, Yu, W. Haung, Yu, Xiao-Fang, Yu, Zhengping, Yuan, Junying, Yuan, Zhi-Min, Yue, Beatrice Y.J.T., Yue, Jianbo, Yue, Zhenyu, Zacks, David N., Zacksenhaus, Eldad, Zaffaroni, Nadia, Zaglia, Tania, Zakeri, Zahra, Zecchini, Vincent, Zeng, Jinsheng, Zeng, Min, Zeng, Qi, Zervos, Antonis S., Zhang, Donna D., Zhang, Fan, Zhang, Guo, Zhang, Guo-Chang, Zhang, Hao, Zhang, Hong, Zhang, Hongbing, Zhang, Jian, Zhang, Jiangwei, Zhang, Jianhua, Zhang, Jing-Pu, Zhang, Li, Zhang, Lin, Zhang, Long, Zhang, Ming-Yong, Zhang, Xiangnan, Zhang, Xu Dong, Zhang, Yan, Zhang, Yang, Zhang, Yanjin, Zhang, Yingmei, Zhang, Yunjiao, Zhao, Mei, Zhao, Wei-Li, Zhao, Xiaonan, Zhao, Yan G., Zhao, Ying, Zhao, Yongchao, Zhao, Yu-Xia, Zhao, Zhendong, Zhao, Zhizhuang J., Zheng, Dexian, Zheng, Xi-Long, Zheng, Xiaoxiang, Zhivotovsky, Bori, Zhong, Qing, Zhou, Guang-Zhou, Zhou, Guofei, Zhou, Huiping, Zhou, Shu-Feng, Zhou, Xu-Jie, Zhu, Hongxin, Zhu, Hua, Zhu, Wei-Guo, Zhu, Wenhua, Zhu, Xiao-Feng, Zhu, Yuhua, Zhuang, Shi-Mei, Zhuang, Xiaohong, Ziparo, Elio, Zois, Christos E., Zoladek, Teresa, Zong, Wei-Xing, Zorzano, Antonio, and Zughaier, Susu M.
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Molecular Biology ,Cell Biology ,Settore BIO/06 - Anatomia Comparata E Citologia - Abstract
non presente
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- 2016
5. In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning
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Formentini L, Pereira M. P. Sánchez-Cenizo L. Santacatterina F. Lucas J. J. Navarro C. Martínez-Serrano A. Cuezva J. M.
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Male ,Neurons ,Behavior, Animal ,Neurotoxins ,Mutation, Missense ,Brain ,Apoptosis ,Mice, Transgenic ,Mitochondrial Proton-Translocating ATPases ,Quinolinic Acid ,Gene Expression Regulation, Enzymologic ,Oxidative Phosphorylation ,Mitochondria ,Mice ,Models, Animal ,Animals ,Humans ,Promoter Regions, Genetic ,Reactive Oxygen Species ,Glycolysis ,Metabolic Networks and Pathways ,Signal Transduction - Abstract
A key transducer in energy conservation and signaling cell death is the mitochondrial H(+)-ATP synthase. The expression of the ATPase inhibitory factor 1 (IF1) is a strategy used by cancer cells to inhibit the activity of the H(+)-ATP synthase to generate a ROS signal that switches on cellular programs of survival. We have generated a mouse model expressing a mutant of human IF1 in brain neurons to assess the role of the H(+)-ATP synthase in cell death in vivo. The expression of hIF1 inhibits the activity of oxidative phosphorylation and mediates the shift of neurons to an enhanced aerobic glycolysis. Metabolic reprogramming induces brain preconditioning affording protection against quinolinic acid-induced excitotoxicity. Mechanistically, preconditioning involves the activation of the Akt/p70S6K and PARP repair pathways and Bcl-xL protection from cell death. Overall, our findings provide the first in vivo evidence highlighting the H(+)-ATP synthase as a target to prevent neuronal cell death.
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- 2014
6. Changes in the activity of ‘active’ pyruvate dehydrogenase complex in the newborn of normal and diabetic rats
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Chitra, C. I., Cuezva, J. M., and Patel, M. S.
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- 1985
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7. In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning
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Formentini, L., primary, Pereira, M. P., additional, Sanchez-Cenizo, L., additional, Santacatterina, F., additional, Lucas, J. J., additional, Navarro, C., additional, Martinez-Serrano, A., additional, and Cuezva, J. M., additional
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- 2014
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8. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers
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Sánchez-Aragó, M, primary, Formentini, L, additional, Martínez-Reyes, I, additional, García-Bermudez, J, additional, Santacatterina, F, additional, Sánchez-Cenizo, L, additional, Willers, I M, additional, Aldea, M, additional, Nájera, L, additional, Juarránz, Á, additional, López, E C, additional, Clofent, J, additional, Navarro, C, additional, Espinosa, E, additional, and Cuezva, J M, additional
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- 2013
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9. Control of the translational efficiency of beta-F1-ATPase mRNA depends on the regulation of a protein that binds the 3' untranslated region of the mRNA
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Izquierdo, J M and Cuezva, J M
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Base Sequence ,Transcription, Genetic ,ADP-Ribosylation Factors ,Molecular Sequence Data ,Ribonuclease H ,Chromosome Mapping ,Oligonucleotides, Antisense ,Rats ,Proton-Translocating ATPases ,Liver ,GTP-Binding Proteins ,Protein Biosynthesis ,Receptors, Adrenergic, beta ,Animals ,Cattle ,RNA, Messenger ,Cloning, Molecular ,Carrier Proteins ,Research Article ,Adenylyl Cyclases ,Protein Binding - Abstract
The expression of the nucleus-encoded beta-F1-ATPase gene of oxidative phosphorylation is developmentally regulated in the liver at both the transcriptional and posttranscriptional levels. In this study we have analyzed the potential mechanisms that control the cytoplasmic expression of beta-F1-ATPase mRNA during liver development. Remarkably, a full-length 3' untranslated region (UTR) of the transcript is required for its efficient in vitro translation. When the 3' UTR of beta-F1-ATPase mRNA is placed downstream of a reporter construct, it functions as a translational enhancer. In vitro translation experiments with full-length beta-F1-ATPase mRNA and with a chimeric reporter construct containing the 3' UTR of beta-F1-ATPase mRNA suggested the existence of an inhibitor of beta-F1-ATPase mRNA translation in the fetal liver. Electrophoretic mobility shift assays and UV cross-linking experiments allowed the identification of an acutely regulated protein (3'betaFBP) of the liver that binds at the 3' UTR of beta-F1-ATPase mRNA. The developmental profile of 3'betaFBP parallels the reported changes in the translational efficiency of beta-F1-ATPase mRNA during development. Fractionation of fetal liver extracts revealed that the inhibitory activity of beta-F1-ATPase mRNA translation cofractionates with 3'-UTR band-shifting activity. Compared to other tissues of the adult rat, kidney and spleen extracts showed very high expression levels of 3'betaFBP. Translation of beta-F1-ATPase mRNA in the presence of kidney and spleen extracts further supported a translational inhibitory role for 3'betaFBP. Mapping experiments and a deletion mutant of the 3' UTR revealed that the cis-acting element for binding 3'betaFBP is located within a highly conserved region of the 3' UTR of mammalian beta-F1-ATPase mRNAs. Overall, we have identified a mechanism of translational control that regulates the rapid postnatal differentiation of liver mitochondria.
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- 1997
10. The bioenergetic signature of lung adenocarcinomas is a molecular marker of cancer diagnosis and prognosis
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Cuezva, J. M., primary
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- 2004
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11. Control of the translational efficiency of beta-F1-ATPase mRNA depends on the regulation of a protein that binds the 3' untranslated region of the mRNA
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Izquierdo, J M, primary and Cuezva, J M, additional
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- 1997
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12. Mammalian adaptation to extrauterine environment: mitochondrial functional impairment caused by prematurity
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Valcarce, C, primary, Izquierdo, J M, additional, Chamorro, M, additional, and Cuezva, J M, additional
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- 1994
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13. Postnatal mitochondrial differentiation in rat liver. Regulation by thyroid hormones of the beta-subunit of the mitochondrial F1-ATPase complex.
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Izquierdo, J M, primary, Luis, A M, additional, and Cuezva, J M, additional
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- 1990
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14. The alpha regulatory subunit of the mitochondrial F1-ATPase complex is a heat-shock protein. Identification of two highly conserved amino acid sequences among the alpha-subunits and molecular chaperones.
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Luis, A M, primary, Alconada, A, additional, and Cuezva, J M, additional
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- 1990
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15. A conserved mechanism for controlling the translation of beta-F1-ATPase mRNA between the fetal liver and cancer cells.
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de Heredia, M L, Izquierdo, J M, and Cuezva, J M
- Abstract
To characterize the mechanisms governing the biogenesis of mitochondria in cancer, we studied the mitochondrial phenotype and the mechanisms controlling the expression of the beta subunit of the mitochondrial H(+)-ATP synthase (beta-F1-ATPase) gene in the rat FAO and AS30D hepatomas. When compared with normal adult rat liver, the relative cellular content of the mitochondrial beta-F1-ATPase and glutamate dehydrogenase, as well as of mitochondrial DNA, was severely reduced in both cell lines. A paradoxical increase in the cellular abundance of beta-F1-ATPase mRNA was observed in cancer cells. Run-on transcription assays and the estimation of mRNA half-lives revealed that the increased abundance of beta-F1-ATPase mRNA results from the stabilization of the transcript in cancer. In vitro translation assays revealed a specific inhibition of the synthesis of the beta-precursor when translation reactions were carried out in the presence of extracts derived from cancer cells. The inhibitory effect was recapitulated using an RNA chimera that contained the 3'-untranslated region of beta-F1-ATPase mRNA. Hepatoma extracts also contained an increased activity of the developmentally regulated translation-inhibitory proteins that bind the 3'-untranslated region of beta-F1-ATPase mRNA. The results indicate that the expression of this gene in hepatoma cells is controlled by the same mechanisms that regulate its expression in the liver during fetal development.
- Published
- 2000
16. Postnatal development of rat liver mitochondrial functions. The roles of protein synthesis and of adenine nucleotides.
- Author
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Valcarce, C, Navarrete, R M, Encabo, P, Loeches, E, Satrústegui, J, and Cuezva, J M
- Abstract
It has been proposed that the acquisition of efficient energy-transducing mitochondria after birth is mediated by an ATP-dependent mechanism “that causes the rapid maturation of mitochondria without requiring either transcription or translation” (Pollak, J. K., and Sutton, R. (1980) Trends Biochem. Sci. 5, 23-27). Investigation of developmental changes in rat liver mitochondria during the first 6 postnatal h showed that fetal mitochondria had low State 4, State 3, and uncoupled rates of respiration, inefficient coupling between respiration and phosphorylation, and low membrane potentials and proton electrochemical gradients under State 4 conditions. In contrast, hepatic mitochondria from 1-h-old neonates showed increased respiratory control and ADP/O ratios and adult proton electrochemical gradient and membrane potential values. In parallel with these changes, mitochondria became enriched in adenine nucleotides and underwent a 50% reduction in matrix volume. During the first postnatal hour, an increase in mitochondrial succinic dehydrogenase, cytochrome c oxidase, and F1-ATPase activities takes place in the neonatal liver concurrent with a preferential postnatal increase in the in vivo rates of protein synthesis for mitochondrial proteins. In particular, the amount of F1-ATPase increased from 109 +/- 9 to 206 +/- 5 ng/microgram of mitochondrial protein in the first hour of postnatal life. Inhibitors of cytosolic protein synthesis present during the first 2 h of life blocked the postnatal increase in respiratory control and ADP/O ratios, succinic dehydrogenase activity, and F1-ATPase content; but they had no effect on the increase in adenine nucleotide concentrations and mitochondrial volume contraction. This indicates that the acquisition of an efficient coupling between respiration and phosphorylation is dependent on de novo protein synthesis and cannot be brought about by the postnatal increase in adenine nucleotides. The increase of State 4 and uncoupled rates of respiration during the first 2 postnatal h was resistant to protein synthesis inhibitors. We suggest that the postnatal increase in these parameters is due to the reduction of mitochondrial volume occurring during that time, which, in turn, may be triggered by the concurrent enrichment in adenine nucleotides.
- Published
- 1988
- Full Text
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17. Postnatal hypoglycaemia and gluconeogenesis in the newborn rat. Delayed onset of gluconeogenesis in prematurely delivered newborns
- Author
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Fernández, E, Valcarce, C, Cuezva, J M, and Medina, J M
- Abstract
The concentrations of glucose and lactate in the blood and of liver glycogen, and the phosphoenolpyruvate carboxykinase activity in liver and kidney of term and preterm newborn rats, were studied during the first 6 h post partum. Rates of lactate turnover and gluconeogenesis in vivo from [U-14C]lactate at 3 h and 6 h post partum were also quantified. The development of the prolonged postnatal hypoglycaemia observed after birth in the premature newborn rat is associated with lower rates of glucose production through glycogenolysis and gluconeogenesis; liver glycogenolysis was the main contributing factor to the glucose available during the neonatal period studied in both groups. Delayed induction of liver phosphoenolpyruvate carboxykinase activity was observed in premature newborn rats. Renal phosphoenolpyruvate carboxykinase activity increased 72% from birth in preterm newborns, but only a 25% increase was found in term newborns during the same experimental period. The gluconeogenesis in vivo from [U-14C]lactate paralleled the appearance of cytosolic phosphoenolpyruvate carboxykinase activity in the liver of both groups of newborns. Blood lactate concentrations remained higher in preterm than in term newborns. The postnatal utilization of lactate via the gluconeogenic pathway in either group of newborns was always less than 20% of the total lactate used. The results presented are discussed in relation to the development of postnatal hypoglycaemia and gluconeogenesis in the premature newborn rat.
- Published
- 1983
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18. Changing patterns of transcriptional and post-transcriptional control of beta-F1-ATPase gene expression during mitochondrial biogenesis in liver.
- Author
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Izquierdo, J M, Ricart, J, Ostronoff, L K, Egea, G, and Cuezva, J M
- Abstract
To elucidate the mechanisms that regulate the expression of nuclear genes during biogenesis of mammalian mitochondria, the expression pattern of the beta-subunit of the ATP synthase gene has been characterized in rat liver between day 20 in utero and 12 weeks postnatal. The parallelism existing between transcriptional activity of the gene and the amount of beta-F1-ATPase protein in liver indicates that proliferation of mitochondria is controlled at the transcriptional level. On the other hand, an increased stability (4-5-fold) of beta-F1-ATPase mRNA during early neonatal life as well as a rapid postnatal activation of translation rates affecting mitochondrial proteins appear to control mitochondrial differentiation. Immunoelectron microscopy of the F1-ATPase complex during liver development revealed that the rapid postnatal increase in the in vivo rate of F1-ATPase synthesis was mostly used for functional differentiation of pre-existing organelles (Valcarce, C., Navarrete, R. M., Encabo, P., Loeches, E., Satrústegui, J., and Cuezva, J. M. (1988) J. Biol Chem. 263, 7767-7775). The findings support that beta-F1-ATPase mRNA decay is developmentally regulated in liver, indicating that gene expression is also controlled at this level during physiological transitions that affect biogenesis of mitochondria.
- Published
- 1995
19. PLASMA-METABOLITE AND SKIN-PROTEIN SIGNATURES OF CHARCOT-MARIE-TOOTH 1A PROVIDE MOLECULAR MARKERS OF DISEASE AND SUGGEST FUTURE THERAPEUTIC INTERVENTIONS
- Author
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Soldevilla, B., Cuevas-Martin, C., Clara Ibañez, Alberti, M. A., Simo, C., Santacatterina, F., Casasnovas, C., Marquez, C., Sevilla, T., Pascual, S. I., Sanchez-Arago, M., Espinos, Palau, F., Cuezva, J. M., and Treat-Cmt Consortium
20. The bioenergetic signature of cancer: a marker of tumor progression
- Author
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Cuezva, J. M., Krajewska, M., Heredia, M. L., Krajewski, S., Santamaría, G., Kim, H., Zapata, J. M., Hiroyuki Marusawa, Chamorro, M., and Reed, J. C.
21. Postnatal Glycogenolysis and Gluconeogenesis in Glucagon-Treated Premature Newborn Rats.
- Author
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Luis, A. M., Valcarce, C., and Cuezva, J. M.
- Published
- 1988
- Full Text
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22. Reverse phase protein microarray technology to provide new diagnostic markers of metabolism in rare diseases.
- Author
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Santacatterina, F., Navarro, C., Sánchez-Arago, M., Martin, M. A., and Cuezva, J. M.
- Subjects
PROTEIN microarrays ,METABOLISM ,RARE diseases - Abstract
An abstract of the article "Reverse phase protein microarray technology to provide new diagnostic markers of metabolism in rare diseases," by F. Santacatterina and colleagues is presented.
- Published
- 2015
23. Prognostic implications of markers of the metabolic phenotype in human cutaneous melanoma.
- Author
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Nájera L, Alonso-Juarranz M, Garrido M, Ballestín C, Moya L, Martínez-Díaz M, Carrillo R, Juarranz A, Rojo F, Cuezva JM, and Rodríguez-Peralto JL
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Biomarkers, Tumor metabolism, Cell Line, Tumor, Disease Progression, Disease-Free Survival, Female, Glycolysis, Humans, Male, Melanocytes cytology, Melanocytes metabolism, Melanoma metabolism, Melanoma pathology, Mice, Middle Aged, Mitochondria metabolism, Prognosis, Retrospective Studies, Skin cytology, Skin Neoplasms metabolism, Skin Neoplasms pathology, Xenograft Model Antitumor Assays, Young Adult, Biomarkers, Tumor analysis, Energy Metabolism, Melanoma mortality, Skin pathology, Skin Neoplasms mortality
- Abstract
Background: Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer., Objectives: To investigate the role of the mitochondrial proteins, β-subunit of the H
+ -ATP synthase (β-F1-ATPase), and heat-shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression., Materials and Methods: The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81-61-PA) and highly (C8161-HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation., Results: The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease-free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4-1·2) is an independent predictor for overall survival., Conclusions: A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation., (© 2018 British Association of Dermatologists.)- Published
- 2019
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24. In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder.
- Author
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Gallego-Villar L, Rivera-Barahona A, Cuevas-Martín C, Guenzel A, Pérez B, Barry MA, Murphy MP, Logan A, Gonzalez-Quintana A, Martín MA, Medina S, Gil-Izquierdo A, Cuezva JM, Richard E, and Desviat LR
- Subjects
- Animals, Antioxidants metabolism, DNA, Mitochondrial genetics, Disease Models, Animal, Homeostasis, Humans, Hydrogen Peroxide metabolism, Lipid Peroxidation genetics, Methylmalonyl-CoA Decarboxylase metabolism, Mice, Mitochondria metabolism, Mitochondria pathology, Oxidation-Reduction, Propionic Acidemia pathology, Protein Array Analysis, Reactive Oxygen Species metabolism, Superoxides metabolism, Methylmalonyl-CoA Decarboxylase genetics, Mitochondria genetics, Oxidative Stress genetics, Propionic Acidemia genetics
- Abstract
Accumulation of toxic metabolites has been described to inhibit mitochondrial enzymes, thereby inducing oxidative stress in propionic acidemia (PA), an autosomal recessive metabolic disorder caused by the deficiency of mitochondrial propionyl-CoA carboxylase. PA patients exhibit neurological deficits and multiorgan complications including cardiomyopathy. To investigate the role of mitochondrial dysfunction in the development of these alterations we have used a hypomorphic mouse model of PA that mimics the biochemical and clinical hallmarks of the disease. We have studied the tissue-specific bioenergetic signature by Reverse Phase Protein Microarrays and analysed OXPHOS complex activities, mtDNA copy number, oxidative damage, superoxide anion and hydrogen peroxide levels. The results show decreased levels and/or activity of several OXPHOS complexes in different tissues of PA mice. An increase in mitochondrial mass and OXPHOS complexes was observed in brain, possibly reflecting a compensatory mechanism including metabolic reprogramming. mtDNA depletion was present in most tissues analysed. Antioxidant enzymes were also found altered. Lipid peroxidation was present along with an increase in hydrogen peroxide and superoxide anion production. These data support the hypothesis that oxidative damage may contribute to the pathophysiology of PA, opening new avenues in the identification of therapeutic targets and paving the way for in vivo evaluation of compounds targeting mitochondrial biogenesis or reactive oxygen species production., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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25. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy.
- Author
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López-Erauskin J, Galino J, Ruiz M, Cuezva JM, Fabregat I, Cacabelos D, Boada J, Martínez J, Ferrer I, Pamplona R, Villarroya F, Portero-Otín M, Fourcade S, and Pujol A
- Subjects
- ATP Binding Cassette Transporter, Subfamily D, Member 1, ATP-Binding Cassette Transporters genetics, Adrenoleukodystrophy genetics, Animals, Brain metabolism, Cells, Cultured, DNA, Mitochondrial, Fibroblasts metabolism, Free Radicals metabolism, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria genetics, Oxidation-Reduction, Oxidative Stress, Spinal Cord metabolism, ATP-Binding Cassette Transporters metabolism, Adrenoleukodystrophy metabolism, Fatty Acids pharmacology, Mitochondria metabolism, Oxidative Phosphorylation, Peroxisomes metabolism
- Abstract
X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disorder of the nervous system characterized by axonopathy in spinal cords and/or cerebral demyelination, adrenal insufficiency and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. The disease is caused by malfunction of the ABCD1 gene, which encodes a peroxisomal transporter of VLCFAs or VLCFA-CoA. In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy. We have formerly shown that an excess of the VLCFA C26:0 induces oxidative damage, which underlies the axonal degeneration exhibited by the Abcd1(-) mice. In the present study, we sought to investigate the noxious effects of C26:0 on mitochondria function. Our data indicate that in X-ALD patients' fibroblasts, excess of C26:0 generates mtDNA oxidation and specifically impairs oxidative phosphorylation (OXPHOS) triggering mitochondrial ROS production from electron transport chain complexes. This correlates with impaired complex V phosphorylative activity, as visualized by high-resolution respirometry on spinal cord slices of Abcd1(-) mice. Further, we identified a marked oxidation of key OXPHOS system subunits in Abcd1(-) mouse spinal cords at presymptomatic stages. Altogether, our results illustrate some of the mechanistic intricacies by which the excess of a fatty acid targeted to peroxisomes activates a deleterious process of oxidative damage to mitochondria, leading to a multifaceted dysfunction of this organelle. These findings may be of relevance for patient management while unveiling novel therapeutic targets for X-ALD.
- Published
- 2013
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26. Reverse phase protein microarrays quantify and validate the bioenergetic signature as biomarker in colorectal cancer.
- Author
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Aldea M, Clofent J, Núñez de Arenas C, Chamorro M, Velasco M, Berrendero JR, Navarro C, and Cuezva JM
- Subjects
- Adenocarcinoma mortality, Adenocarcinoma pathology, Aged, Biomarkers, Tumor metabolism, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Prognosis, Proportional Hazards Models, Adenocarcinoma metabolism, Biomarkers, Tumor analysis, Colorectal Neoplasms metabolism, Energy Metabolism physiology, Protein Array Analysis methods
- Abstract
A reverse phase protein microarray approach has been applied to quantify proteins of energy metabolism in normal and tumor biopsies of colorectal cancer (CRC) patients. The metabolic proteome of CRC specimens revealed a profound shift towards and enhanced glycolytic phenotype and concurrent mitochondrial alteration. The metabolic signature discriminated CRC patients with highly significant differences in overall and disease-free prognosis. The quantification of the bioenergetic signature of the tumor offers a relevant biomarker of CRC that could contribute in the handling of these patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2011
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27. Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts.
- Author
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Morán M, Rivera H, Sánchez-Aragó M, Blázquez A, Merinero B, Ugalde C, Arenas J, Cuezva JM, and Martín MA
- Subjects
- Acidosis genetics, Acidosis metabolism, Acidosis pathology, Adenosine Triphosphate metabolism, Blotting, Western, Cells, Cultured, Epilepsy genetics, Epilepsy metabolism, Epilepsy pathology, Flow Cytometry, Fluorescent Antibody Technique, Glycolysis, Humans, Infant, Leukoencephalopathies genetics, Leukoencephalopathies metabolism, Leukoencephalopathies pathology, Male, Mitochondria drug effects, Mitochondrial Diseases metabolism, NADH Dehydrogenase metabolism, Oxygen Consumption, RNA, Messenger genetics, RNA, Messenger metabolism, Reactive Oxygen Species metabolism, Reverse Transcriptase Polymerase Chain Reaction, Skin cytology, Skin metabolism, Electron Transport Complex I metabolism, Energy Metabolism, Fibroblasts enzymology, Mitochondria metabolism, Mitochondrial Diseases genetics, Mutation genetics, NADH Dehydrogenase genetics
- Abstract
Background: Complex I (CI) deficiency is the most frequent cause of OXPHOS disorders. Recent studies have shown increases in reactive oxygen species (ROS) production and mitochondrial network disturbances in patients' fibroblasts harbouring mutations in CI subunits., Objectives: The present work evaluates the impact of mutations in the NDUFA1 and NDUFV1 genes of CI on mitochondrial bioenergetics and dynamics, in fibroblasts from patients suffering isolated CI deficiency., Results: Decreased oxygen consumption rate and slow growth rate were found in patients with severe CI deficiency. Mitochondrial diameter was slightly increased in patients' cells cultured in galactose or treated with 2'-deoxyglucose without evidence of mitochondrial fragmentation. Expression levels of the main proteins involved in mitochondrial dynamics, OPA1, MFN2, and DRP1, were slightly augmented in all patients' cells lines. The study of mitochondrial dynamics showed delayed recovery of the mitochondrial network after treatment with the uncoupler carbonyl cyanide m-chlorophenyl hydrazone (cccp) in patients with severe CI deficiency. Intracellular ROS levels were not increased neither in glucose nor galactose medium in patients' fibroblasts., Conclusion: Our main finding was that severe CI deficiency in patients harbouring mutations in the NDUFA1 and NDUFV1 genes is linked to a delayed mitochondrial network recovery after cccp treatment. However, the CI deficiency is neither associated with massive mitochondrial fragmentation nor with increased ROS levels. The different genetic backgrounds of patients with OXPHOS disorders would explain, at least partially, differences in the pathophysiological manifestations of CI deficiency., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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28. Immunolocalization of a novel cholesteryl ester hydrolase in the endoplasmic reticulum of murine and human hepatocytes.
- Author
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Fresnedo O, De Heredia ML, Martínez MJ, Cristóbal S, Rejas MT, Cuezva JM, and Ochoa B
- Subjects
- Animals, Calcium-Binding Proteins metabolism, Calnexin, Culture Techniques, Humans, Immunoblotting, Immunohistochemistry, Mice, Microscopy, Confocal, Microscopy, Immunoelectron, Rats, Subcellular Fractions enzymology, Tissue Distribution, Cholesterol Esters metabolism, Endoplasmic Reticulum enzymology, Hepatocytes enzymology, Hydrolases metabolism
- Abstract
We have recently purified a cholesteryl ester hydrolase (CEH) from rat liver microsomes. Antibodies raised against the purified protein specifically reacted with a 106-kd protein and neutralized 90% of the CEH activity of rat liver microsomes (J Lipid Res 1999;40:715-725). In this work we have used the anti-CEH antibody to study both the subcellular distribution of the protein in hepatocytes as well as its tissue-specific expression in rat. Western blotting of subcellular fractions obtained from isolated rat hepatocytes revealed that the immunoreactive 106-kd CEH was exclusively localized in microsomes. The antibody also recognized a 106-kd protein in microsomes from mouse and human liver but not from rat nonparenchymal liver cells. Confocal microscopy of HepG2 cells revealed that CEH immunoreactive material colocalized with calnexin, a marker of the endoplasmic reticulum. Furthermore, high-resolution immunoelectron microscopy of rat liver thin sections exclusively localized the CEH immunoreactivity to the endoplasmic reticulum of the hepatocyte. No CEH immunoreactivity was observed in microsomes derived from adrenal glands, ovaries, testis, pancreas, intestine, white adipose tissue, mammary gland, lung, spleen, brain, aorta, and macrophages. We report a CEH localized to the endoplasmic reticulum, erCEH, in the mammalian hepatocyte. The subcellular localization and tissue-restricted pattern of expression of erCEH suggests that it might have unique functions in liver cholesterol metabolism.
- Published
- 2001
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29. 3'-untranslated regions of oxidative phosphorylation mRNAs function in vivo as enhancers of translation.
- Author
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Di Liegro CM, Bellafiore M, Izquierdo JM, Rantanen A, and Cuezva JM
- Subjects
- 3' Untranslated Regions, Animals, Blotting, Western, Cell Line, Cell Nucleus metabolism, DNA-Binding Proteins metabolism, Electron Transport Complex IV genetics, Electron Transport Complex IV metabolism, Electrophoresis, Polyacrylamide Gel, Genes, Reporter, Green Fluorescent Proteins, Kidney metabolism, Liver metabolism, Luminescent Proteins metabolism, Microscopy, Fluorescence, Mitochondria metabolism, Plasmids metabolism, Proton-Translocating ATPases genetics, Proton-Translocating ATPases metabolism, Rats, Transcription Factors metabolism, Transcription, Genetic, Transfection, Mitochondrial Proteins, Nuclear Proteins, Oxidative Phosphorylation, Protein Biosynthesis, RNA, Messenger genetics
- Abstract
Recent findings have indicated that the 3'-untranslated region (3'-UTR) of the mRNA encoding the beta-catalytic subunit of the mitochondrial H(+)-ATP synthase has an in vitro translation-enhancing activity (TEA) [Izquierdo and Cuezva, Mol. Cell. Biol. (1997) 17, 5255-5268; Izquierdo and Cuezva, Biochem. J. (2000) 346, 849-855]. In the present work, we have expressed chimaeric plasmids that encode mRNA variants of green fluorescent protein in normal rat kidney and liver clone 9 cells to determine whether the 3'-UTRs of nuclear-encoded mRNAs involved in the biogenesis of mitochondria have an intrinsic TEA. TEA is found in the 3'-UTR of the mRNAs encoding the alpha- and beta-subunits of the rat H(+)-ATP synthase complex, as well as in subunit IV of cytochrome c oxidase. No TEA is present in the 3'-UTR of the somatic mRNA encoding rat mitochondrial transcription factor A. Interestingly, the TEA of the 3'-UTR of mRNAs of oxidative phosphorylation is different, depending upon the cell type analysed. These data provide the first in vivo evidence of a novel cell-specific mechanism for the control of the translation of mRNAs required in mitochondrial function.
- Published
- 2000
30. Internal-ribosome-entry-site functional activity of the 3'-untranslated region of the mRNA for the beta subunit of mitochondrial H+-ATP synthase.
- Author
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Izquierdo JM and Cuezva JM
- Subjects
- Animals, Base Sequence, DNA Primers, Oxidative Phosphorylation, Prostaglandin-Endoperoxide Synthases genetics, Protein Biosynthesis, RNA, Messenger genetics, Rats, 3' Untranslated Regions, Mitochondria, Liver enzymology, Proton-Translocating ATPases genetics, RNA, Messenger metabolism, Ribosomes metabolism
- Abstract
Translation in vitro of the mammalian nucleus-encoded mRNA for the beta subunit of mitochondrial H(+)-ATP synthase (beta-mRNA) of oxidative phosphorylation is promoted by a 150 nt translational enhancer sequence in the 3'-untranslated region (3' UTR). Titration of the eukaryotic initiation factor eIF4E with cap analogue revealed that translation of capped beta-mRNA was pseudo-cap independent. The 3' UTR of beta-mRNA stimulates the translation of heterologous uncapped mRNA species, both when the 3' UTR is placed at the 3' end and at the 5' end of the transcripts. The 3' UTRs of the alpha subunit of mitochondrial H(+)-ATP synthase (alpha-F1-ATPase) and subunit IV of cytochrome c oxidase (COX IV) mRNA species, other nucleus-encoded transcripts of oxidative phosphorylation, do not have the same activity in translation as the 3' UTR of beta-mRNA. On dicistronic RNA species, the 3' UTR of beta-mRNA, and to a smaller extent that of COX IV mRNA, is able to promote the translation of the second cistron to a level comparable to the activity of internal ribosome entry sites (IRESs) described in picornavirus mRNA species. These results indicate that the 3' UTRs of certain mRNA species of oxidative phosphorylation have IRES-like functional activity. Riboprobes of the active 3' UTRs on dicistronic assays formed specific RNA-protein complexes when cross-linked by UV to proteins of the lysate, suggesting that cytoplasmic translation of the mRNA species bearing an active 3' UTR is assisted by specific RNA-protein interactions.
- Published
- 2000
31. Migration of mitochondria to viral assembly sites in African swine fever virus-infected cells.
- Author
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Rojo G, Chamorro M, Salas ML, Viñuela E, Cuezva JM, and Salas J
- Subjects
- Animals, Chlorocebus aethiops, Microtubules physiology, Proton-Translocating ATPases metabolism, Vero Cells, African Swine Fever Virus physiology, Mitochondria physiology, Virus Assembly
- Abstract
An examination by electron microscopy of the viral assembly sites in Vero cells infected with African swine fever virus showed the presence of large clusters of mitochondria located in their proximity. These clusters surround viral factories that contain assembling particles but not factories where only precursor membranes are seen. Immunofluorescence microscopy revealed that these accumulations of mitochondria are originated by a massive migration of the organelle to the virus assembly sites. Virus infection also promoted the induction of the mitochondrial stress-responsive proteins p74 and cpn 60 together with a dramatic shift in the ultrastructural morphology of the mitochondria toward that characteristic of actively respiring organelles. The clustering of mitochondria around the viral factory was blocked in the presence of the microtubule-disassembling drug nocodazole, indicating that these filaments are implicated in the transport of the mitochondria to the virus assembly sites. The results presented are consistent with a role for the mitochondria in supplying the energy that the virus morphogenetic processes may require and make of the African swine fever virus-infected cell a paradigm to investigate the mechanisms involved in the sorting of mitochondria within the cell.
- Published
- 1998
- Full Text
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32. Mitochondrial biogenesis in the liver during development and oncogenesis.
- Author
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Cuezva JM, Ostronoff LK, Ricart J, López de Heredia M, Di Liegro CM, and Izquierdo JM
- Subjects
- Animals, Carcinoma, Hepatocellular genetics, Energy Metabolism, Gene Expression Regulation, Liver growth & development, Oxidative Phosphorylation, Proton-Translocating ATPases genetics, Carcinoma, Hepatocellular metabolism, Cell Transformation, Neoplastic, Liver metabolism, Mitochondria metabolism
- Abstract
The analysis of the expression of oxidative phosphorylation genes in the liver during development reveals the existence of two biological programs involved in the biogenesis of mitochondria. Differentiation is a short-term program of biogenesis that is controlled at post-transcriptional levels of gene expression and is responsible for the rapid changes in the bioenergetic phenotype of mitochondria. In contrast, proliferation is a long-term program controlled both at the transcriptional and post-transcriptional levels of gene expression and is responsible for the increase in mitochondrial mass in the hepatocyte. Recently, a specific subcellular structure involved in the localization and control of the translation of the mRNA encoding the beta-catalytic subunit of the H(+)-ATP synthase (beta-mRNA) has been identified. It is suggested that this structure plays a prominent role in the control of mitochondrial biogenesis at post-transcriptional levels. The fetal liver has many phenotypic manifestations in common with highly glycolytic tumor cells. In addition, both have a low mitochondrial content despite a paradoxical increase in the cellular representation of oxidative phosphorylation transcripts. Based on the paradigm provided by the fetal liver we hypothesize that the aberrant mitochondrial phenotype of fast-growing hepatomas represents a reversion to a fetal program of expression of oxidative phosphorylation genes by the activation, or increased expression, of an inhibitor of beta-mRNA translation.
- Published
- 1997
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33. Subcellular structure containing mRNA for beta subunit of mitochondrial H+-ATP synthase in rat hepatocytes is translationally active.
- Author
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Ricart J, Egea G, Izquierdo JM, San Martín C, and Cuezva JM
- Subjects
- Animals, Animals, Newborn, DNA, Complementary genetics, HSP70 Heat-Shock Proteins analysis, In Situ Hybridization, Male, Mitochondria, Liver metabolism, Phosphoproteins analysis, Protein Folding, Proton-Translocating ATPases biosynthesis, Proton-Translocating ATPases chemistry, RNA, Messenger metabolism, Rats, Rats, Wistar, Ribosomal Proteins analysis, Liver metabolism, Organelles metabolism, Protein Biosynthesis, Proton-Translocating ATPases genetics, RNA, Messenger genetics
- Abstract
We have recently reported that the nuclear-encoded mRNA for the beta subunit of mitochondrial H+-ATP synthase (beta-mRNA) is localized in rounded, electron-dense clusters in the cytoplasm of rat hepatocytes. Clusters of beta-mRNA are often found in close proximity to mitochondria. These findings suggested a role for these structures in controlling the cytoplasmic expression and sorting of the encoded mitochondrial precursor. Here we have addressed the question of whether the structures containing beta-mRNA are translationally active. For this purpose a combination of high-resolution in situ hybridization and immunocytochemical procedures was used. Three different co-localization criteria showed that beta-mRNA-containing structures always revealed positive immunoreactive signals for mitochondrial H+-ATP synthase (F1-ATPase), ribosomal and hsc70 proteins. Furthermore, clusters show evidence in situ of developmental changes in the translational efficiency of the beta-mRNA. These findings suggest that structures containing beta-mRNA are translationally active irrespective of their cytoplasmic location. The immunocytochemical quantification of the cytoplasmic presentation of hsc70 in the hepatocyte reveals that approx. 86% of the protein has a dispersed distribution pattern. However, the remaining hsc70 is presented in clusters of which only half reveal positive hybridization for beta-mRNA. The interaction of hsc70 with the beta-F1-ATPase precursor protein is documented by the co-localization of F1-ATPase immunoreactive material within cytoplasmic clusters of hsc70 and by the co-immunoprecipitation of hsc70 with the beta-subunit precursor from liver post-mitochondrial supernatants. Taken together, these results suggest a role for hsc70 in the translation/sorting pathway of the mammalian precursor of the beta-F1-ATPase protein.
- Published
- 1997
- Full Text
- View/download PDF
34. Highways for protein delivery to the mitochondria.
- Author
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Lithgow T, Cuezva JM, and Silver PA
- Subjects
- Animals, Biological Transport, Cell Nucleus genetics, Cell Nucleus metabolism, Cytoplasm metabolism, Drosophila genetics, Drosophila metabolism, Fungal Proteins genetics, Fungal Proteins metabolism, Mammals, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Biosynthesis, Protein Processing, Post-Translational, Proteins genetics, RNA, Messenger genetics, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Mitochondria metabolism, Proteins metabolism, RNA, Messenger metabolism, Saccharomyces cerevisiae Proteins
- Abstract
Messenger RNA (mRNA) localisation is one of the prime mechanisms to ensure protein localisation in the cytoplasm of polarised embryonic cells, and has been well-studied in the development of Xenopus and Drosophila embryos. But what of other cells? Here, we discuss whether the directed transport of mRNA out of the nucleus, following cytoplasmic highways to a specified organelle in the cytoplasm, might also contribute to the exquisite fidelity of protein targeting observed in all eukaryotic cells.
- Published
- 1997
- Full Text
- View/download PDF
35. mRNA encoding the beta-subunit of the mitochondrial F1-ATPase complex is a localized mRNA in rat hepatocytes.
- Author
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Egea G, Izquierdo JM, Ricart J, San Martín C, and Cuezva JM
- Subjects
- Animals, Animals, Newborn, Cytoplasm genetics, Immunohistochemistry, In Situ Hybridization, Liver cytology, Male, Mitochondria, Liver genetics, Protein Conformation, Protein Precursors isolation & purification, Proton-Translocating ATPases isolation & purification, RNA, Messenger ultrastructure, Rats, Rats, Wistar, Cell Compartmentation, Gene Expression Regulation, Developmental, Liver physiology, Proton-Translocating ATPases genetics, RNA, Messenger isolation & purification
- Abstract
Subcellular mRNA localization has emerged as a mechanism for regulation of gene expression and protein-sorting pathways. Here we describe the different cytoplasmic presentation in rat hepatocytes of two nuclear mRNA species encoding subunits alpha and beta of the mitochondrial F1-ATPase complex. alpha-F1-ATPase mRNA is dispersed and scattered in the cytoplasm. In contrast, beta-F1-ATPase mRNA appears in rounded electron-dense clusters, often in close proximity to mitochondria. Hybridization experiments with beta2-microglobulin and beta-actin cDNA species reveal an expected subcellular distribution pattern of the mRNA species and a non-clustered appearance. Development does not alter the presentation of beta-F1-ATPase mRNA hybrids, although it affects the relative abundance of beta-F1-ATPase mRNA clusters in the cytoplasm of the hepatocyte. These findings illustrate in vivo the existence of two different sorting pathways for the nuclear-encoded mRNA species of mitochondrial proteins. High-resolution immunocytochemistry and immunoprecipitation experiments allowed the identification of the beta-subunit precursor in the cytoplasm of the hepatocyte, also suggesting a post-translational import pathway for this precursor protein. It is suggested that the localization of beta-F1-ATPase mRNA in a subcellular structure of the hepatocyte might have implications for the control of gene expression at post-transcriptional levels during mitochondrial biogenesis in mammals.
- Published
- 1997
- Full Text
- View/download PDF
36. Identification of sequence similarity between 60 kDa and 70 kDa molecular chaperones: evidence for a common evolutionary background?
- Author
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Flores AI and Cuezva JM
- Subjects
- Amino Acid Sequence, Animals, Blotting, Western, Chaperonin 60 immunology, Cross Reactions, Databases, Factual, Drosophila melanogaster cytology, Drosophila melanogaster embryology, Drosophila melanogaster metabolism, Electrophoresis, Gel, Two-Dimensional, HSP70 Heat-Shock Proteins immunology, Molecular Sequence Data, Protein Structure, Secondary, Protein Structure, Tertiary, Proton-Translocating ATPases immunology, Sequence Homology, Amino Acid, Chaperonin 60 genetics, Evolution, Molecular, HSP70 Heat-Shock Proteins genetics, Proton-Translocating ATPases genetics
- Abstract
Recent findings support the premise that chaperonins (60 kDa stress-proteins) and alpha-subunits of F-type ATPases (alpha-ATPase) are evolutionary related protein families. Two-dimensional gel patterns of synthesized proteins in unstressed and heat-shocked embryonic Drosophila melanogaster SL2 cells revealed that antibodies raised against the alpha-subunit of the F1-ATPase complex from rat liver recognize an inducible p71 member of the 70 kDa stress-responsive protein family. Molecular recognition of this stress-responsive 70 kDa protein by antibodies raised against the F1-ATPase alpha-subunit suggests the possibility of partial sequence similarity within these ATP-binding protein families. A multiple sequence alignment between alpha-ATPases and 60 kDa and 70 kDa molecular chaperones is presented. Statistical evaluation of sequence similarity reveals a significant degree of sequence conservation within the three protein families. The finding suggests a common evolutionary origin for the ATPases and molecular chaperone protein families of 60 kDa and 70 kDa, despite the lack of obvious structural resemblance between them.
- Published
- 1997
- Full Text
- View/download PDF
37. Transient activation of mitochondrial translation regulates the expression of the mitochondrial genome during mammalian mitochondrial differentiation.
- Author
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Ostronoff LK, Izquierdo JM, Enríquez JA, Montoya J, and Cuezva JM
- Subjects
- Animals, Animals, Newborn, Female, Fetus, Gene Expression Regulation, Developmental, Liver embryology, Liver growth & development, Mammals, Pregnancy, Proton-Translocating ATPases biosynthesis, RNA biosynthesis, RNA, Mitochondrial, Rats, Rats, Wistar, Transcription, Genetic, Aging metabolism, DNA, Mitochondrial metabolism, Gene Expression Regulation, Enzymologic, Mitochondria, Liver metabolism, Protein Biosynthesis
- Abstract
Regulation of the expression of the nuclear-encoded beta-subunit of H(+)-ATP synthase (beta-F1-ATPase) gene of oxidative phosphorylation during differentiation of liver mitochondria is mainly exerted at two post-transcriptional levels affecting both the half-life [Izquierdo, Ricart, Ostronoff, Egea and Cuezva (1995) J. Biol. Chem. 270, 10342-10350] and translational efficiency [Luis, Izquierdo, Ostronoff, Salinas, Santarén and Cuezva (1993) J. Biol. Chem. 268, 1868-1875] of the transcript. Herein, we have studied the expression of the mitochondrial (mt) genome during differentiation of rat liver mitochondria in an effort to elucidate the mechanisms of nucleo-mitochondrial cross-talk during biogenesis of the organelle. Estimation of the relative cellular representation of met-DNA in liver reveals a negligible increase in mt-DNA copy number during organelle differentiation. Concurrently, the lack of changes in transcription rates of the mt-DNA "in organello', as well as in steady-state levels of the mt-transcripts, suggests that organelle differentiation is not controlled by an increase in transcription of the mt-genome. However, translation rates in isolated mitochondria revealed a transient 2-fold increase immediately after birth. Interestingly, the transient activation of mitochondrial translation at this stage of liver development is dependent on the synthesis of proteins in cytoplasmic polyribosomes. These findings support the hypothesis that the expression of nuclear and mitochondrial genes during biogenesis of mammalian mitochondria is developmentally regulated by a post-transcriptional mechanism that involves concerted translational control of both genomes.
- Published
- 1996
- Full Text
- View/download PDF
38. mt-mRNA stability regulates the expression of the mitochondrial genome during liver development.
- Author
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Ostronoff LK, Izquierdo JM, and Cuezva JM
- Subjects
- Age Factors, Animals, Animals, Newborn, Cell Nucleus physiology, Dactinomycin pharmacology, Female, Gene Expression Regulation, Developmental drug effects, Proton-Translocating ATPases genetics, RNA, Messenger genetics, RNA, Mitochondrial, Rats, Rats, Wistar, Liver growth & development, Mitochondria, Liver metabolism, RNA metabolism
- Abstract
We have recently reported that regulation of the expression of the nuclear-encoded beta-F1-ATPase gene during development of rat liver is exerted also by the control of beta-F1-ATPase mRNA decay (Izquierdo, J.M., Ricart, J., Ostronoff, L.K., Egea, G. and Cuezva, J.M. (1995) J. Biol. Chem. 270, 10342-10350). In this paper, we report that high steady-state levels of the mitochondrial encoded mRNAs for subunits of the ATP synthase (ATP 6-8) in developing liver result from profound changes in the stability of the mitochondrial transcripts. The results strongly suggest that developmental regulation of nuclear and mitochondrial genes during biogenesis of mammalian mitochondria is concertedly controlled by a posttranscriptional mechanism that involves the regulation of mRNA degradation of both genomes.
- Published
- 1995
- Full Text
- View/download PDF
39. Cpn60 is exclusively localized into mitochondria of rat liver and embryonic Drosophila cells.
- Author
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Martin CS, Flores AI, and Cuezva JM
- Subjects
- Amino Acid Sequence, Animals, Artifacts, Cell Nucleus chemistry, Cells, Cultured, Drosophila melanogaster embryology, Drosophila melanogaster ultrastructure, Embryo, Nonmammalian metabolism, Hot Temperature, Microscopy, Immunoelectron, Molecular Sequence Data, Rats, Rats, Wistar, Subcellular Fractions chemistry, Chaperonin 60 chemistry, Drosophila melanogaster chemistry, Mitochondria, Liver chemistry
- Abstract
Several reports have claimed that the mitochondrial chaperonin cpn60, or a close homolog, is also present in some other subcellular compartments of the eukaryotic cell. Immunoelectron microscopy studies, using a polyclonal serum against cpn60, revealed that the protein is exclusively localized within the mitochondria of rat liver and embryonic Drosophila cells (SL2). Furthermore, no cpn60 immunoreactive material could be found within the nucleus of SL2 cells subjected to a 1 h 37 degrees C heat-shock treatment. In contrast to these findings, immunoelectron microscopy studies, using a cpn60 monoclonal antibody, revealed mitochondrial and extramitochondrial (plasma membrane, nucleus) immunoreactive material in rat liver cells. Surprisingly, the monoclonal antibody also reacted with fixed proteins of the mature red blood cell. The monoclonal antibody, as well as cpn60 polyclonal sera, only recognize mitochondrial cpn60 in Western blots of liver proteins. Furthermore, none of the cpn60 antibodies used in this study recognized blotted proteins from rat red blood cells. Therefore, we suggest that the reported extramitochondrial localization of cpn60 in metazoan cells may be due to cross-reactivity of some of cpn60 antibodies with conformational epitopes also present in distantly related cpn60 protein homologs that are preserved during fixation procedures of the cells.
- Published
- 1995
- Full Text
- View/download PDF
40. Hypothyroidism affects the expression of the beta-F1-ATPase gene and limits mitochondrial proliferation in rat liver at all stages of development.
- Author
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Izquierdo JM, Jiménez E, and Cuezva JM
- Subjects
- Animals, Animals, Suckling, Female, Gene Expression Regulation, Developmental, Hypothyroidism pathology, Mitochondria, Liver enzymology, Mitochondria, Liver pathology, Pregnancy, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Wistar, Thyroid Hormones metabolism, Hypothyroidism enzymology, Hypothyroidism genetics, Proton-Translocating ATPases genetics
- Abstract
In order to analyze the role of thyroid hormones in mitochondrial biogenesis, we have studied the expression pattern of the beta subunit of the mitochondrial ATP-synthase complex in liver and in isolated mitochondria during postnatal development of hypothyroid rats. Chemically induced hypothyroidism promoted a significant reduction in body and liver masses at all stages of development. Furthermore, plasma 3,5,3'-triiodo-L-thyronine (T3) and 3,5,3',5'-tetraiodo-L-thyronine (T4) concentrations were significantly reduced in hypothyroid animals when compared to euthyroid animals. Remarkably, steady-state beta-F1-ATPase mRNA levels in livers of hypothyroid animals showed an approximately 50% reduction when compared to age-matched euthyroid rats at all stages of development. The relative amounts of beta-F1-ATPase protein determined in isolated mitochondria of 1-day-old and adult hypothyroid animals were similar to those determined in mitochondria of age-matched euthyroids, indicating that hypothyroidism does not affect organelle differentiation in the liver of suckling and adult rats. In contrast, the relative amount of beta-F1-ATPase protein in liver homogenates varied (0-30% reduction) due to the hypothyroid condition during development. These findings suggest the existence of compensatory mechanisms operating at the translational and/or post-translational levels which promote proliferation of mitochondria in the hypothyroid liver. However, when the liver mass was considered, hypothyroidism significantly reduced overall mitochondrial proliferation in rat liver. Interestingly, the effects of thyroid hormones on the biogenesis of the ATP synthase complex at latter stages of development provide an example in which the hypothyroid condition limits the expression of the nuclear-encoded gene with no apparent effect on the expression of the mitochondrial-encoded genes (ATP synthase subunits 6-8).
- Published
- 1995
- Full Text
- View/download PDF
41. Antibodies against F1-ATPase alpha-subunit recognize mitochondrial chaperones. Evidence for an evolutionary relationship between chaperonin and ATPase protein families.
- Author
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Alconada A, Flores AI, Blanco L, and Cuezva JM
- Subjects
- Amino Acid Sequence, Animals, Antibodies immunology, Bacterial Proteins immunology, Cells, Cultured, Chaperonin 60, Chaperonins, Cross Reactions, Drosophila melanogaster, Heat-Shock Proteins genetics, Heat-Shock Proteins immunology, Mitochondria, Liver enzymology, Molecular Sequence Data, Peptide Fragments immunology, Proteins genetics, Proton-Translocating ATPases chemistry, Proton-Translocating ATPases genetics, Rats, Rats, Wistar, Sequence Homology, Amino Acid, Biological Evolution, Proteins immunology, Proton-Translocating ATPases immunology
- Abstract
Antibodies raised against two synthetic peptides from rat liver F1-ATPase alpha-subunit sequence recognized two main heat-shock proteins from Drosophila (p71 and p56) and rat liver (p74 and p54) cells. One of the antisera showed a 20-fold higher reactivity toward Escherichia coli GroEL chaperonin than toward the alpha-subunit purified from Drosophila. Indirect immunofluorescence microscopy and subcellular fractionation experiments located both mammalian heat-shock proteins in the mitochondria. The recent findings of functional homology between chaperonins and alpha-subunits, together with the unsuspected immunological reactivity of two mitochondrial molecular chaperones toward antisera derived from two different sequence motifs of the alpha-subunit, strongly argue in favor of the existence of an evolutionary relationship between chaperonins and alpha-subunits. The complete sequence alignment of F-type ATPase alpha-subunits and chaperonins revealed the existence of eleven most conserved regions (approximately 30% of each protein sequence) with an overall amino acid identity of 20 +/- 2% and similarity of 39 +/- 4%. A search of protein data bases with three different consensus sequences derived from this alignment identified a significant proportion of proteins belonging only to these two protein families. Since the alpha-subunit protein family is evolutionary related to the other catalytic (A and beta) and regulatory (B) subunits of V- and F-type ATPases, the homology reported herein allowed us to analyze, in the chaperonin sequences, the conservation of critical residues involved in nucleotide binding. These data support the hypothesis that chaperonins and the major subunits of V- and F-type ATPases are evolutionary related.
- Published
- 1994
42. Evidence of post-transcriptional regulation in mammalian mitochondrial biogenesis.
- Author
-
Izquierdo JM and Cuezva JM
- Subjects
- Animals, Gene Expression Regulation, Enzymologic, Male, Protein Biosynthesis, RNA, Messenger analysis, Rats, Rats, Wistar, Tissue Distribution, Transcription, Genetic, Mitochondria physiology, Proton-Translocating ATPases biosynthesis, RNA Processing, Post-Transcriptional
- Abstract
We have previously shown that the nuclear-encoded gene's expression of mitochondrial beta-subunit of the F1-ATPase complex in rat liver is regulated at the translational level (Luis, A.M., Izquierdo, J.M., Ostronoff, L.K., Santarén, J., Salinas, M., and Cuezva, J.M. (1993) J. Biol. Chem. 268, 1868-1875). In this paper we report that the different steady-state levels of ATP synthase beta subunit mRNA detected in rat tissues are not paralleled by a proportional content of immunodetectable beta-F1-ATPase protein. The results suggest that tissue-specific transcriptional and post-transcriptional mechanisms contribute to differential mitochondrial biogenesis in mammalian cells. On the other hand, steady-state mRNA levels of the mitochondrial encoded ATP synthase subunits (ATP 6+8) indicate that nuclear and mitochondrial-encoded transcripts for this complex are in close relation, that is, the expression of both nuclear and mitochondrial genes is coordinated in all tissues examined.
- Published
- 1993
- Full Text
- View/download PDF
43. Thyroid hormones promote transcriptional activation of the nuclear gene coding for mitochondrial beta-F1-ATPase in rat liver.
- Author
-
Izquierdo JM and Cuezva JM
- Subjects
- Animals, Animals, Newborn, Cell Nucleus metabolism, Female, Pregnancy, Proton-Translocating ATPases metabolism, Rats, Rats, Wistar, Gene Expression Regulation, Enzymologic, Mitochondria, Liver enzymology, Proton-Translocating ATPases genetics, Thyroid Hormones physiology, Transcription, Genetic
- Abstract
Thyroid hormones acutely regulate gene expression of the beta-catalytic subunit of the mitochondrial F1-ATPase complex in the liver of hypothyroid rat neonates at either a transcriptional and/or post-transcriptional level [(1990) J. Biol. Chem. 265, 9090-9097]. Administration at birth of various thyroid hormone doses to hypothyroid newborn rats promote a rapid (1 h) increase in liver steady-state amounts of both beta-F1-ATPase protein and mRNA. Induction of the beta-F1-ATPase mRNA is coincident with an elevation in gene transcription detected using nascent RNA chains synthesized by isolated nuclei. These results suggest that thyroid hormones induction of postnatal mitochondrial differentiation in the liver of hypothyroid rat neonates is mostly triggered by transcriptional regulation of beta-F1-ATPase gene.
- Published
- 1993
- Full Text
- View/download PDF
44. A chaperonin protein module involved in recognition of interactive protein surfaces?
- Author
-
Alconada A and Cuezva JM
- Subjects
- Amino Acid Sequence, Bacterial Proteins genetics, Chaperonins, Consensus Sequence, Fungal Proteins genetics, Molecular Sequence Data, Plant Proteins genetics, Proton-Translocating ATPases genetics, Proteins genetics
- Published
- 1993
- Full Text
- View/download PDF
45. Examination of processing of the rat liver mitochondrial F1-ATPase beta subunit precursor protein by high-resolution 2D-gel electrophoresis.
- Author
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Santarén JF, Alconada A, and Cuezva JM
- Subjects
- Animals, Electrophoresis, Gel, Two-Dimensional, Isoelectric Point, Molecular Weight, Rats, Mitochondria, Liver enzymology, Protein Precursors metabolism, Protein Processing, Post-Translational, Proton-Translocating ATPases metabolism
- Abstract
We report the one-step processing of the rat liver beta-F1-ATPase precursor protein, as examined by high resolution 2D-gel electrophoresis. Proteolytic cleavage of the positively charged mitochondrial targeting signal of the precursor promotes decreases in both the molecular weight (approximately 3 kDa) and the isoelectric point (approximate 0.2 pH unit) of the protein. The results obtained illustrate the usefulness of this technique, since it takes advantage of both results of the maturation process, for molecular characterization of the processing of mitochondrial precursor proteins.
- Published
- 1993
- Full Text
- View/download PDF
46. Translational regulation of mitochondrial differentiation in neonatal rat liver. Specific increase in the translational efficiency of the nuclear-encoded mitochondrial beta-F1-ATPase mRNA.
- Author
-
Luis AM, Izquierdo JM, Ostronoff LK, Salinas M, Santarén JF, and Cuezva JM
- Subjects
- Animals, Blotting, Western, Cell Nucleus metabolism, Eukaryotic Initiation Factor-2 metabolism, Polyribosomes metabolism, RNA, Messenger metabolism, Rats, Rats, Wistar, Tubulin genetics, Animals, Newborn, Mitochondria, Liver enzymology, Protein Biosynthesis, Proton-Translocating ATPases genetics, RNA, Messenger genetics
- Abstract
Postnatal (1-h) mitochondrial differentiation in normal neonatal rat liver is regulated at the translational level (Izquierdo, J. M., Luis, A. M., and Cuezva, J. M. (1990) J. Biol. Chem. 265, 9090-9097). The rapid postnatal increase in liver global rate of protein synthesis preferentially affects mitochondrial proteins (Valcarce, C., Navarrete, R. M., Encabo, P., Loeches, E., Satrústegui, J., and Cuezva, J. M. (1988) J. Biol. Chem. 263, 7767-7775). Analysis of polysome profiles and determination of both eukaryotic initiation factor 2 (eIF-2) activity and amount of eIF-2 beta protein in the liver of fetal and 1-h-old neonatal rats, indicate a rapid activation of translation initiation without changes in the amount of the translational machinery available between both stages of liver development. Appearance of a more acidic eIF-2 beta-subunit form in two-dimensional Western blots from 1-h-old rat livers suggests that covalently regulated modifications of the initiation factor phosphoproteins might be responsible for increased translation in the neonatal liver. On the other hand, preferential cytosolic translation of the mitochondrial nuclear-encoded beta-F1-ATPase mRNA at this stage of liver development is accomplished by (i) the antenatal accumulation of this mRNA in the fetal liver in 5-6-fold excess than that found in adults, although fetal liver beta-F1-ATPase mRNA shows negligible translational efficiency when compared to the adult counterpart; (ii) a 2-fold increase of the stored beta-F1-ATPase mRNA being rapidly mobilized into cytosolic polyribosomes, and (iii) a 3-fold increase in the in vitro determined translational efficiency of beta-F1-ATPase mRNA. Increased translational efficiency of beta-F1-ATPase mRNA at 1-h postnatal is specific for the nuclear-encoded template since beta-tubulin mRNA did not show any postnatal alteration in its translational efficiency. The results presented suggest that developmental changes in the poly(A)+ RNA fraction or in the reporter template itself are responsible for the increased and preferential translation of the nuclear-encoded mitochondrial mRNAs needed for mitochondrial differentiation and, thus, for mammalian adaptation to the extrauterine environment.
- Published
- 1993
47. Molecular chaperones and the biogenesis of mitochondria and peroxisomes.
- Author
-
Cuezva JM, Flores AI, Liras A, Santarén JF, and Alconada A
- Subjects
- Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Protein Conformation, Protein Precursors chemistry, Proteins chemistry, Proteins metabolism, Signal Transduction physiology, Microbodies metabolism, Mitochondria metabolism, Protein Precursors metabolism, Trans-Activators physiology
- Abstract
A review of the proteinaceous machinery involved in protein sorting pathways and protein folding and assembly in mitochondria and peroxisomes is presented. After considering the various sorting pathways and targeting signals of mitochondrial and peroxisomal proteins, we make a comparative dissection of the protein factors involved in: i) the stabilization of cytosolic precursor proteins in a translocation competent conformation; ii) the membrane import apparatus of mitochondria and peroxisomes; iii) the processing of mitochondrial precursor proteins, and the eventual processing of certain peroxisomal precursor, in the interior of the organelles; and iv) the requirement of molecular chaperones for appropriate folding and assembly of imported proteins in the matrix of both organelles. Those aspects of mitochondrial biogenesis that have developed rapidly during the last few years, such as the requirement of molecular chaperones, are stressed in order to stimulate further parallel investigations aimed to understand the origin, biochemistry, molecular biology and pathology of peroxisomes. In this regard, a brief review of findings from our group and others is presented in which the role of the F1-ATPase alpha-subunit is pointed out as a molecular chaperone of mitochondria and chloroplasts. In addition, data are presented that could question our previous indication that the immunoreactive protein found in the rat liver peroxisomes is due to the presence of the F1-ATPase alpha-subunit.
- Published
- 1993
- Full Text
- View/download PDF
48. Interaction of adenine nucleotides with the adenine nucleotide translocase regulates the developmental changes in proton conductance of the inner mitochondrial membrane.
- Author
-
Valcarce C and Cuezva JM
- Subjects
- Adenosine Triphosphate pharmacology, Animals, Animals, Newborn, Atractyloside analogs & derivatives, Atractyloside pharmacology, Cell Membrane Permeability drug effects, Electric Conductivity, Guanosine Diphosphate pharmacology, Liver embryology, Rats, Adenine Nucleotides metabolism, Intracellular Membranes physiology, Liver growth & development, Mitochondria, Liver physiology, Mitochondrial ADP, ATP Translocases metabolism, Protons
- Abstract
2-h-old neonatal liver mitochondria, when depleted of adenine nucleotides, showed an 'ohmic' current-voltage relationship and a higher passive proton permeability of the membrane, resembling fetal mitochondrial behaviors for the proton conductance. Incubation of fetal mitochondria with ATP, GDP or carboxyatractyloside promoted a significant reduction in the passive proton permeability of the membrane and the appearance of the characteristic biphasic behavior for the proton conductance. It is concluded that the postnatal increase in intramitochondrial adenine nucleotide concentration promotes, by the interaction of the nucleotides with the adenine nucleotide translocase, the reduction in the passive proton permeability of the mitochondrial membrane, allowing efficient energy conservation in the neonatal liver.
- Published
- 1991
- Full Text
- View/download PDF
49. Rapid postnatal developmental changes in the passive proton permeability of the inner membrane in rat liver mitochondria.
- Author
-
Valcarce C, Vitorica J, Satrústegui J, and Cuezva JM
- Subjects
- Animals, Animals, Newborn, Membrane Potentials, Protons, Rats, Rats, Inbred Strains, Fetus, Intracellular Membranes physiology, Mitochondria, Liver physiology
- Abstract
Titration of mitochondrial respiration against the membrane potential with the inhibitor malonate has been carried out during the perinatal period in isolated rat liver mitochondria. Neonatal and adult mitochondria exhibited the characteristic "nonohmic" behavior for the proton conductance (CmH+). In contrast, fetal mitochondria exhibited an "anomalous" "ohmic" behavior for CmH+. The calculated passive proton permeability of the membrane undergoes a profound reduction during the first postnatal hour. The results reported demonstrate that the hypothesis [Pollak, J.K. & Sutton, R. (1980) Trends Biochem. Sci. 5, 23-27] of the existence of a "leaky" mitochondria in the fetal rat liver, and of its sudden neonatal change towards a state of higher energy conservation of the proton electrochemical gradient, is correct.
- Published
- 1990
50. Immunological detection of the mitochondrial F1-ATPase alpha subunit in the matrix of rat liver peroxisomes. A protein involved in organelle biogenesis?
- Author
-
Cuezva JM, Santarén JF, González P, Valcarce C, Luis AM, and Izquierdo JM
- Subjects
- Animals, Centrifugation, Density Gradient, Fetus enzymology, Liver embryology, Microbodies ultrastructure, Microscopy, Immunoelectron, Mitochondria, Liver ultrastructure, Proton-Translocating ATPases analysis, Rats, Subcellular Fractions enzymology, Microbodies enzymology, Mitochondria, Liver enzymology, Proton-Translocating ATPases physiology
- Abstract
Rat liver peroxisomes contain in their matrix the alpha-subunit of the mitochondrial F1-ATPase complex. The identification of this protein in liver peroxisomes has been achieved by immunoelectron microscopy and subcellular fractionation. No beta-subunit of the mitochondrial F1-ATPase complex was detected in the peroxisomal fractions obtained in sucrose gradients or in Nycodenz pelletted peroxisomes. The consensus peroxisomal targeting sequence (Ala-Lys-Leu) is found at the carboxy terminus of the mature alpha-subunit from bovine heart and rat liver mitochondria. Due to the dual subcellular localization of the alpha-subunit and to the structural homologies that exist between this protein and molecular chaperones [(1990) Biol. Chem. 265, 7713-7716] it is suggested that the protein should perform another functional role(s) in both organelles, plus to its characteristic involvement in the regulation of mitochondrial ATPase activity.
- Published
- 1990
- Full Text
- View/download PDF
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