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1. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases

Author

Connolly, Niamh MC, Theurey, Pierre, Adam-Vizi, Vera, Bazan, Nicolas G, Bernardi, Paolo, Bolaños, Juan P, Culmsee, Carsten, Dawson, Valina L, Deshmukh, Mohanish, Duchen, Michael R, Düssmann, Heiko, Fiskum, Gary, Galindo, Maria F, Hardingham, Giles E, Hardwick, J Marie, Jekabsons, Mika B, Jonas, Elizabeth A, Jordán, Joaquin, Lipton, Stuart A, Manfredi, Giovanni, Mattson, Mark P, McLaughlin, BethAnn, Methner, Axel, Murphy, Anne N, Murphy, Michael P, Nicholls, David G, Polster, Brian M, Pozzan, Tullio, Rizzuto, Rosario, Satrústegui, Jorgina, Slack, Ruth S, Swanson, Raymond A, Swerdlow, Russell H, Will, Yvonne, Ying, Zheng, Joselin, Alvin, Gioran, Anna, Moreira Pinho, Catarina, Watters, Orla, Salvucci, Manuela, Llorente-Folch, Irene, Park, David S, Bano, Daniele, Ankarcrona, Maria, Pizzo, Paola, and Prehn, Jochen HM

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurodegenerative, Aging, Acquired Cognitive Impairment, Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Humans, Mitochondria, Models, Biological, Neurodegenerative Diseases, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field.

Published
2018

2. Apoptotic cell death in disease—Current understanding of the NCCD 2023

Author

Vitale, Ilio, primary, Pietrocola, Federico, additional, Guilbaud, Emma, additional, Aaronson, Stuart A., additional, Abrams, John M., additional, Adam, Dieter, additional, Agostini, Massimiliano, additional, Agostinis, Patrizia, additional, Alnemri, Emad S., additional, Altucci, Lucia, additional, Amelio, Ivano, additional, Andrews, David W., additional, Aqeilan, Rami I., additional, Arama, Eli, additional, Baehrecke, Eric H., additional, Balachandran, Siddharth, additional, Bano, Daniele, additional, Barlev, Nickolai A., additional, Bartek, Jiri, additional, Bazan, Nicolas G., additional, Becker, Christoph, additional, Bernassola, Francesca, additional, Bertrand, Mathieu J. M., additional, Bianchi, Marco E., additional, Blagosklonny, Mikhail V., additional, Blander, J. Magarian, additional, Blandino, Giovanni, additional, Blomgren, Klas, additional, Borner, Christoph, additional, Bortner, Carl D., additional, Bove, Pierluigi, additional, Boya, Patricia, additional, Brenner, Catherine, additional, Broz, Petr, additional, Brunner, Thomas, additional, Damgaard, Rune Busk, additional, Calin, George A., additional, Campanella, Michelangelo, additional, Candi, Eleonora, additional, Carbone, Michele, additional, Carmona-Gutierrez, Didac, additional, Cecconi, Francesco, additional, Chan, Francis K. -M., additional, Chen, Guo-Qiang, additional, Chen, Quan, additional, Chen, Youhai H., additional, Cheng, Emily H., additional, Chipuk, Jerry E., additional, Cidlowski, John A., additional, Ciechanover, Aaron, additional, Ciliberto, Gennaro, additional, Conrad, Marcus, additional, Cubillos-Ruiz, Juan R., additional, Czabotar, Peter E., additional, D’Angiolella, Vincenzo, additional, Daugaard, Mads, additional, Dawson, Ted M., additional, Dawson, Valina L., additional, De Maria, Ruggero, additional, De Strooper, Bart, additional, Debatin, Klaus-Michael, additional, Deberardinis, Ralph J., additional, Degterev, Alexei, additional, Del Sal, Giannino, additional, Deshmukh, Mohanish, additional, Di Virgilio, Francesco, additional, Diederich, Marc, additional, Dixon, Scott J., additional, Dynlacht, Brian D., additional, El-Deiry, Wafik S., additional, Elrod, John W., additional, Engeland, Kurt, additional, Fimia, Gian Maria, additional, Galassi, Claudia, additional, Ganini, Carlo, additional, Garcia-Saez, Ana J., additional, Garg, Abhishek D., additional, Garrido, Carmen, additional, Gavathiotis, Evripidis, additional, Gerlic, Motti, additional, Ghosh, Sourav, additional, Green, Douglas R., additional, Greene, Lloyd A., additional, Gronemeyer, Hinrich, additional, Häcker, Georg, additional, Hajnóczky, György, additional, Hardwick, J. Marie, additional, Haupt, Ygal, additional, He, Sudan, additional, Heery, David M., additional, Hengartner, Michael O., additional, Hetz, Claudio, additional, Hildeman, David A., additional, Ichijo, Hidenori, additional, Inoue, Satoshi, additional, Jäättelä, Marja, additional, Janic, Ana, additional, Joseph, Bertrand, additional, Jost, Philipp J., additional, Kanneganti, Thirumala-Devi, additional, Karin, Michael, additional, Kashkar, Hamid, additional, Kaufmann, Thomas, additional, Kelly, Gemma L., additional, Kepp, Oliver, additional, Kimchi, Adi, additional, Kitsis, Richard N., additional, Klionsky, Daniel J., additional, Kluck, Ruth, additional, Krysko, Dmitri V., additional, Kulms, Dagmar, additional, Kumar, Sharad, additional, Lavandero, Sergio, additional, Lavrik, Inna N., additional, Lemasters, John J., additional, Liccardi, Gianmaria, additional, Linkermann, Andreas, additional, Lipton, Stuart A., additional, Lockshin, Richard A., additional, López-Otín, Carlos, additional, Luedde, Tom, additional, MacFarlane, Marion, additional, Madeo, Frank, additional, Malorni, Walter, additional, Manic, Gwenola, additional, Mantovani, Roberto, additional, Marchi, Saverio, additional, Marine, Jean-Christophe, additional, Martin, Seamus J., additional, Martinou, Jean-Claude, additional, Mastroberardino, Pier G., additional, Medema, Jan Paul, additional, Mehlen, Patrick, additional, Meier, Pascal, additional, Melino, Gerry, additional, Melino, Sonia, additional, Miao, Edward A., additional, Moll, Ute M., additional, Muñoz-Pinedo, Cristina, additional, Murphy, Daniel J., additional, Niklison-Chirou, Maria Victoria, additional, Novelli, Flavia, additional, Núñez, Gabriel, additional, Oberst, Andrew, additional, Ofengeim, Dimitry, additional, Opferman, Joseph T., additional, Oren, Moshe, additional, Pagano, Michele, additional, Panaretakis, Theocharis, additional, Pasparakis, Manolis, additional, Penninger, Josef M., additional, Pentimalli, Francesca, additional, Pereira, David M., additional, Pervaiz, Shazib, additional, Peter, Marcus E., additional, Pinton, Paolo, additional, Porta, Giovanni, additional, Prehn, Jochen H. M., additional, Puthalakath, Hamsa, additional, Rabinovich, Gabriel A., additional, Rajalingam, Krishnaraj, additional, Ravichandran, Kodi S., additional, Rehm, Markus, additional, Ricci, Jean-Ehrland, additional, Rizzuto, Rosario, additional, Robinson, Nirmal, additional, Rodrigues, Cecilia M. P., additional, Rotblat, Barak, additional, Rothlin, Carla V., additional, Rubinsztein, David C., additional, Rudel, Thomas, additional, Rufini, Alessandro, additional, Ryan, Kevin M., additional, Sarosiek, Kristopher A., additional, Sawa, Akira, additional, Sayan, Emre, additional, Schroder, Kate, additional, Scorrano, Luca, additional, Sesti, Federico, additional, Shao, Feng, additional, Shi, Yufang, additional, Sica, Giuseppe S., additional, Silke, John, additional, Simon, Hans-Uwe, additional, Sistigu, Antonella, additional, Stephanou, Anastasis, additional, Stockwell, Brent R., additional, Strapazzon, Flavie, additional, Strasser, Andreas, additional, Sun, Liming, additional, Sun, Erwei, additional, Sun, Qiang, additional, Szabadkai, Gyorgy, additional, Tait, Stephen W. G., additional, Tang, Daolin, additional, Tavernarakis, Nektarios, additional, Troy, Carol M., additional, Turk, Boris, additional, Urbano, Nicoletta, additional, Vandenabeele, Peter, additional, Vanden Berghe, Tom, additional, Vander Heiden, Matthew G., additional, Vanderluit, Jacqueline L., additional, Verkhratsky, Alexei, additional, Villunger, Andreas, additional, von Karstedt, Silvia, additional, Voss, Anne K., additional, Vousden, Karen H., additional, Vucic, Domagoj, additional, Vuri, Daniela, additional, Wagner, Erwin F., additional, Walczak, Henning, additional, Wallach, David, additional, Wang, Ruoning, additional, Wang, Ying, additional, Weber, Achim, additional, Wood, Will, additional, Yamazaki, Takahiro, additional, Yang, Huang-Tian, additional, Zakeri, Zahra, additional, Zawacka-Pankau, Joanna E., additional, Zhang, Lin, additional, Zhang, Haibing, additional, Zhivotovsky, Boris, additional, Zhou, Wenzhao, additional, Piacentini, Mauro, additional, Kroemer, Guido, additional, and Galluzzi, Lorenzo, additional

Published
2023
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3. An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution

Author

Lindner, Andreas Ulrich, primary, Salvucci, Manuela, additional, McDonough, Elizabeth, additional, Cho, Sanghee, additional, Stachtea, Xanthi, additional, O’Connell, Emer P., additional, Corwin, Alex D., additional, Santamaria-Pang, Alberto, additional, Carberry, Steven, additional, Fichtner, Michael, additional, Van Schaeybroeck, Sandra, additional, Laurent-Puig, Pierre, additional, Burke, John P., additional, McNamara, Deborah A., additional, Lawler, Mark, additional, Sood, Anup, additional, Graf, John F., additional, Rehm, Markus, additional, Dunne, Philip D., additional, Longley, Daniel B., additional, Ginty, Fiona, additional, and Prehn, Jochen H. M., additional

Published
2021
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4. Simulating and predicting cellular and in vivo responses of colon cancer to combined treatment with chemotherapy and IAP antagonist Birinapant/TL32711

Author

Ruth E Mooney, Christian T. Hellwig, Daniel B. Longley, Manuela Salvucci, Carla O’Connor, Nyree Crawford, Jochen H. M. Prehn, Frank A. Lincoln, and Markus Rehm

Subjects
0301 basic medicine, Indoles, Colorectal cancer, medicine.medical_treatment, Apoptosis, chemotherapy, Mitochondrial Membrane Transport Proteins, Inhibitor of Apoptosis Proteins, Mice, RNA, Small Interfering, Mice, Inbred BALB C, education.field_of_study, systems biology, Dipeptides, IAP, Oxaliplatin, Intracellular signal transduction, Receptor-Interacting Protein Serine-Threonine Kinases, Colonic Neoplasms, Drug Therapy, Combination, Female, RNA Interference, Fluorouracil, Programmed cell death, Population, Antineoplastic Agents, X-Linked Inhibitor of Apoptosis Protein, colorectal cancer, Inhibitor of apoptosis, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, In vivo, Cell Line, Tumor, medicine, Animals, Humans, education, Molecular Biology, Chemotherapy, Mitochondrial Permeability Transition Pore, business.industry, Cell Biology, Models, Theoretical, medicine.disease, 030104 developmental biology, Cancer research, business, SMAC
Abstract

Apoptosis resistance contributes to treatment failure in colorectal cancer (CRC). New treatments that reinstate apoptosis competency have potential to improve patient outcome but require predictive biomarkers to target them to responsive patient populations. Inhibitor of apoptosis proteins (IAPs) suppress apoptosis, contributing to drug resistance; IAP antagonists such as TL32711 have therefore been developed. We developed a systems biology approach for predicting response of CRC cells to chemotherapy and TL32711 combinations in vitro and in vivo. CRC cells responded poorly to TL32711 monotherapy in vitro; however, co-treatment with 5-Fluorouracil (5-FU) and oxaliplatin enhanced TL32711-induced apoptosis. Notably, cells from genetically identical populations responded highly heterogeneously, with caspases being activated both upstream and downstream of mitochondrial outer membrane permeabilisation (MOMP). These data, combined with quantities of key apoptosis regulators were sufficient to replicate in vitro cell death profiles by mathematical modelling. In vivo, apoptosis protein expression was significantly altered, and mathematical modelling for these conditions predicted higher apoptosis resistance that could nevertheless be overcome by combination of chemotherapy and TL32711. Subsequent experimental observations agreed with these predictions, and the observed effects on tumour growth inhibition correlated robustly with apoptosis competency. We therefore obtained insights into intracellular signal transduction kinetics and their population-based heterogeneities for chemotherapy/TL32711 combinations and provide proof-of-concept that mathematical modelling of apoptosis competency can simulate and predict responsiveness in vivo. Being able to predict response to IAP antagonist-based treatments on the background of cell-to-cell heterogeneities in the future might assist in improving treatment stratification approaches for these emerging apoptosis-targeting agents.

Published
2018

8. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, Lorenzo, primary, Vitale, Ilio, additional, Aaronson, Stuart A., additional, Abrams, John M., additional, Adam, Dieter, additional, Agostinis, Patrizia, additional, Alnemri, Emad S., additional, Altucci, Lucia, additional, Amelio, Ivano, additional, Andrews, David W., additional, Annicchiarico-Petruzzelli, Margherita, additional, Antonov, Alexey V., additional, Arama, Eli, additional, Baehrecke, Eric H., additional, Barlev, Nickolai A., additional, Bazan, Nicolas G., additional, Bernassola, Francesca, additional, Bertrand, Mathieu J. M., additional, Bianchi, Katiuscia, additional, Blagosklonny, Mikhail V., additional, Blomgren, Klas, additional, Borner, Christoph, additional, Boya, Patricia, additional, Brenner, Catherine, additional, Campanella, Michelangelo, additional, Candi, Eleonora, additional, Carmona-Gutierrez, Didac, additional, Cecconi, Francesco, additional, Chan, Francis K.-M., additional, Chandel, Navdeep S., additional, Cheng, Emily H., additional, Chipuk, Jerry E., additional, Cidlowski, John A., additional, Ciechanover, Aaron, additional, Cohen, Gerald M., additional, Conrad, Marcus, additional, Cubillos-Ruiz, Juan R., additional, Czabotar, Peter E., additional, D’Angiolella, Vincenzo, additional, Dawson, Ted M., additional, Dawson, Valina L., additional, De Laurenzi, Vincenzo, additional, De Maria, Ruggero, additional, Debatin, Klaus-Michael, additional, DeBerardinis, Ralph J., additional, Deshmukh, Mohanish, additional, Di Daniele, Nicola, additional, Di Virgilio, Francesco, additional, Dixit, Vishva M., additional, Dixon, Scott J., additional, Duckett, Colin S., additional, Dynlacht, Brian D., additional, El-Deiry, Wafik S., additional, Elrod, John W., additional, Fimia, Gian Maria, additional, Fulda, Simone, additional, García-Sáez, Ana J., additional, Garg, Abhishek D., additional, Garrido, Carmen, additional, Gavathiotis, Evripidis, additional, Golstein, Pierre, additional, Gottlieb, Eyal, additional, Green, Douglas R., additional, Greene, Lloyd A., additional, Gronemeyer, Hinrich, additional, Gross, Atan, additional, Hajnoczky, Gyorgy, additional, Hardwick, J. Marie, additional, Harris, Isaac S., additional, Hengartner, Michael O., additional, Hetz, Claudio, additional, Ichijo, Hidenori, additional, Jäättelä, Marja, additional, Joseph, Bertrand, additional, Jost, Philipp J., additional, Juin, Philippe P., additional, Kaiser, William J., additional, Karin, Michael, additional, Kaufmann, Thomas, additional, Kepp, Oliver, additional, Kimchi, Adi, additional, Kitsis, Richard N., additional, Klionsky, Daniel J., additional, Knight, Richard A., additional, Kumar, Sharad, additional, Lee, Sam W., additional, Lemasters, John J., additional, Levine, Beth, additional, Linkermann, Andreas, additional, Lipton, Stuart A., additional, Lockshin, Richard A., additional, López-Otín, Carlos, additional, Lowe, Scott W., additional, Luedde, Tom, additional, Lugli, Enrico, additional, MacFarlane, Marion, additional, Madeo, Frank, additional, Malewicz, Michal, additional, Malorni, Walter, additional, Manic, Gwenola, additional, Marine, Jean-Christophe, additional, Martin, Seamus J., additional, Martinou, Jean-Claude, additional, Medema, Jan Paul, additional, Mehlen, Patrick, additional, Meier, Pascal, additional, Melino, Sonia, additional, Miao, Edward A., additional, Molkentin, Jeffery D., additional, Moll, Ute M., additional, Muñoz-Pinedo, Cristina, additional, Nagata, Shigekazu, additional, Nuñez, Gabriel, additional, Oberst, Andrew, additional, Oren, Moshe, additional, Overholtzer, Michael, additional, Pagano, Michele, additional, Panaretakis, Theocharis, additional, Pasparakis, Manolis, additional, Penninger, Josef M., additional, Pereira, David M., additional, Pervaiz, Shazib, additional, Peter, Marcus E., additional, Piacentini, Mauro, additional, Pinton, Paolo, additional, Prehn, Jochen H.M., additional, Puthalakath, Hamsa, additional, Rabinovich, Gabriel A., additional, Rehm, Markus, additional, Rizzuto, Rosario, additional, Rodrigues, Cecilia M.P., additional, Rubinsztein, David C., additional, Rudel, Thomas, additional, Ryan, Kevin M., additional, Sayan, Emre, additional, Scorrano, Luca, additional, Shao, Feng, additional, Shi, Yufang, additional, Silke, John, additional, Simon, Hans-Uwe, additional, Sistigu, Antonella, additional, Stockwell, Brent R., additional, Strasser, Andreas, additional, Szabadkai, Gyorgy, additional, Tait, Stephen W.G., additional, Tang, Daolin, additional, Tavernarakis, Nektarios, additional, Thorburn, Andrew, additional, Tsujimoto, Yoshihide, additional, Turk, Boris, additional, Vanden Berghe, Tom, additional, Vandenabeele, Peter, additional, Vander Heiden, Matthew G., additional, Villunger, Andreas, additional, Virgin, Herbert W., additional, Vousden, Karen H., additional, Vucic, Domagoj, additional, Wagner, Erwin F., additional, Walczak, Henning, additional, Wallach, David, additional, Wang, Ying, additional, Wells, James A., additional, Wood, Will, additional, Yuan, Junying, additional, Zakeri, Zahra, additional, Zhivotovsky, Boris, additional, Zitvogel, Laurence, additional, Melino, Gerry, additional, and Kroemer, Guido, additional

Published
2018
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9. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases

Author

Connolly, Niamh M. C., primary, Theurey, Pierre, additional, Adam-Vizi, Vera, additional, Bazan, Nicolas G., additional, Bernardi, Paolo, additional, Bolaños, Juan P., additional, Culmsee, Carsten, additional, Dawson, Valina L., additional, Deshmukh, Mohanish, additional, Duchen, Michael R., additional, Düssmann, Heiko, additional, Fiskum, Gary, additional, Galindo, Maria F., additional, Hardingham, Giles E., additional, Hardwick, J. Marie, additional, Jekabsons, Mika B., additional, Jonas, Elizabeth A., additional, Jordán, Joaquin, additional, Lipton, Stuart A., additional, Manfredi, Giovanni, additional, Mattson, Mark P., additional, McLaughlin, BethAnn, additional, Methner, Axel, additional, Murphy, Anne N., additional, Murphy, Michael P., additional, Nicholls, David G., additional, Polster, Brian M., additional, Pozzan, Tullio, additional, Rizzuto, Rosario, additional, Satrústegui, Jorgina, additional, Slack, Ruth S., additional, Swanson, Raymond A., additional, Swerdlow, Russell H., additional, Will, Yvonne, additional, Ying, Zheng, additional, Joselin, Alvin, additional, Gioran, Anna, additional, Moreira Pinho, Catarina, additional, Watters, Orla, additional, Salvucci, Manuela, additional, Llorente-Folch, Irene, additional, Park, David S., additional, Bano, Daniele, additional, Ankarcrona, Maria, additional, Pizzo, Paola, additional, and Prehn, Jochen H. M., additional

Published
2017
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10. Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate

Author

Caoimhín G. Concannon, Heiko Düssmann, Petronela Weisová, Niamh M. C. Connolly, Helena P. Bonner, David Dávila, Heinrich J. Huber, and Jochen H. M. Prehn

Subjects
Down-Regulation, Apoptosis, AMP-Activated Protein Kinases, Biology, Dephosphorylation, Mice, AMP-activated protein kinase, Proto-Oncogene Proteins, Animals, Phosphorylation, RNA, Small Interfering, Promoter Regions, Genetic, Protein kinase A, Molecular Biology, Protein kinase B, Cells, Cultured, Cell Nucleus, Neurons, Original Paper, Bcl-2-Like Protein 11, TOR Serine-Threonine Kinases, Forkhead Box Protein O3, Membrane Proteins, AMPK, Forkhead Transcription Factors, Cell Biology, Rats, Cell biology, Transcription Factor AP-1, Glucose, Cancer research, FOXO3, biology.protein, RNA Interference, Signal transduction, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Cerebral ischemia and excitotoxic injury induce transient or permanent bioenergetic failure, and may result in neuronal apoptosis or necrosis. We have previously shown that ATP depletion and activation of AMP-activated protein kinase (AMPK) during excitotoxic injury induces neuronal apoptosis by transcription of the pro-apoptotic BH3-only protein, Bim. AMPK, however, also exerts pro-survival functions in neurons. The molecular switches that determine these differential outcomes are not well understood. Using an approach combining biochemistry, single-cell imaging and computational modeling, we here demonstrate that excitotoxic injury activated the bim promoter in a FOXO3-dependent manner. The activation of AMPK reduced AKT activation, and led to dephosphorylation and nuclear translocation of FOXO3. Subsequent mutation studies indicated that bim gene activation during excitotoxic injury required direct FOXO3 phosphorylation by AMPK in the nucleus as a second activation step. Inhibition of this phosphorylation prevented Bim expression and protected neurons against excitotoxic and oxygen/glucose deprivation-induced injury. Systems analysis and computational modeling revealed that these two activation steps defined a coherent feed-forward loop; a network motif capable of filtering any effects of short-term AMPK activation on bim gene induction. This may prevent unwanted AMPK-mediated Bim expression and apoptosis during transient or physiological bioenergetic stress. ispartof: Cell Death and Differentiation vol:19 issue:10 pages:1677-1688 ispartof: location:England status: published

Published
2012

11. MicroRNAs 10a and 10b are potent inducers of neuroblastoma cell differentiation through targeting of nuclear receptor corepressor 2

Author

Kenneth Bryan, Raymond L. Stallings, Jochen H. M. Prehn, Tytus Bernas, Isabella Bray, Karen M. Watters, Niamh H. Foley, and Sudipto Das

Subjects
Neurite, Cellular differentiation, Down-Regulation, Tretinoin, Biology, Transfection, Neuroblastoma, Downregulation and upregulation, Cell Line, Tumor, Humans, Nuclear Receptor Co-Repressor 2, RNA, Small Interfering, Nuclear protein, Molecular Biology, Nuclear receptor co-repressor 2, Neurons, Oncogene Proteins, Original Paper, N-Myc Proto-Oncogene Protein, Nuclear Proteins, Cell Differentiation, Cell Biology, Molecular biology, Cell biology, MicroRNAs, Nuclear receptor, RNA Interference, Signal transduction, Corepressor
Abstract

MicroRNAs function as negative regulators of posttranscriptional gene expression, having major roles in cellular differentiation. Several neuroblastoma cell lines can be induced to undergo differentiation by all-trans-retinoic acid (ATRA) and are used for modeling signaling pathways involved in this process. To identify miRNAs contributing to differentiation, we profiled 364 loci following ATRA treatment of neuroblastoma cell lines and found miR-10a and miR-10b to be highly overexpressed in SK-N-BE, LAN5 and SHSY-5Y. Ectopic overexpression of these miRNAs led to a major reprogramming of the transcriptome and a differentiated phenotype that was similar to that induced by ATRA in each of these cell lines. One of the predicted downregulated miR-10a/b targets was nuclear receptor corepressor 2 (NCOR2), a corepressor of gene transcription, which is known to suppress neurite outgrowth. NCOR2 was experimentally validated as a direct target of miR-10a/b, and siRNA-mediated inhibition of this mRNA alone resulted in neural cell differentiation. Moreover, induction of differentiation could be blocked by ectopic upregulation of NCOR2 using an expression construct lacking the miR-10a/b 3' untranslated region target site. We conclude that miR-10a/b has major roles in the process of neural cell differentiation through direct targeting of NCOR2, which in turn induces a cascade of primary and secondary transcriptional alterations, including the downregulation of MYCN.

Published
2011

12. Dynamics of outer mitochondrial membrane permeabilization during apoptosis

Author

Christian T. Hellwig, Jochen H. M. Prehn, Markus Rehm, Heinrich J. Huber, Heiko Düssmann, and Sergio Anguissola

Subjects
Cell Membrane Permeability, Population, Cell, Apoptosis, Cell Membrane Structures, Models, Biological, TNF-Related Apoptosis-Inducing Ligand, 03 medical and health sciences, 0302 clinical medicine, Single-cell analysis, medicine, Humans, Staurosporine, Enzyme Inhibitors, education, Molecular Biology, Mitosis, 030304 developmental biology, Microscopy, 0303 health sciences, education.field_of_study, biology, Cytochrome c, Cytochromes c, Cell Biology, Flow Cytometry, Cell biology, Kinetics, Cytosol, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mitochondrial Membranes, biology.protein, HeLa Cells, medicine.drug
Abstract

Individual cells within a population undergo apoptosis at distinct, apparently random time points. By analyzing cellular mitotic history, we identified that sibling HeLa cell pairs, in contrast to random cell pairs, underwent apoptosis synchronously. This allowed us to use high-speed cellular imaging to investigate mitochondrial outer membrane permeabilization (MOMP), a highly coordinated, rapid process during apoptosis, at a temporal resolution approximately 100 times higher than possible previously. We obtained new functional and mechanistic insight into the process of MOMP: We were able to determine the kinetics of pore formation in the outer mitochondrial membrane from the initiation phase of cytochrome-c-GFP redistribution, and showed differential pore formation kinetics in response to intrinsic or extrinsic apoptotic stimuli (staurosporine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)). We also detected that the onset of mitochondrial permeabilization frequently proceeded as a wave through the cytosol, and that the frequency of wave occurrence in response to TRAIL was reduced by inhibition of protein kinase CK2. Computational analysis by a partial differential equation model suggested that the spread of permeabilization signals could sufficiently be explained by diffusion-adsorption velocities of locally generated permeabilization inducers. Taken together, our study yielded the first comprehensive analysis of clonal cell-to-cell variability in apoptosis execution and allowed to visualize and explain the dynamics of MOMP in cells undergoing apoptosis.

Published
2009

13. Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

Author

Jochen H. M. Prehn, Donat Kögel, Ekaterini Copanaki, and Robert Schomburg

Subjects
Programmed cell death, Indoles, Transcription, Genetic, Proto-Oncogene Proteins c-jun, Ultraviolet Rays, Mutant, Carbazoles, Apoptosis, PC12 Cells, Amyloid beta-Protein Precursor, Endopeptidases, mental disorders, Gene expression, Amyloid precursor protein, Animals, Aspartic Acid Endopeptidases, Humans, Osteonectin, Phosphorylation, Protein Kinase Inhibitors, Molecular Biology, Psychological repression, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, biology, Kinase, JNK Mitogen-Activated Protein Kinases, Cell Biology, MAP Kinase Kinase Kinases, Molecular biology, Rats, Gene Expression Regulation, Neoplastic, Transcription Factor AP-1, biology.protein, Amyloid Precursor Protein Secretases, Signal Transduction
Abstract

The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip analysis and in vitro kinase assays revealed potent APP-dependent repression of c-Jun, its target gene SPARC and reduced basal c-Jun N-terminal kinase (JNK) activity in PC12 cells overexpressing APP. UV-induced activation of the JNK signalling pathway and subsequent apoptosis were likewise reduced by APP and this effect could be mimicked by the indirect JNK inhibitor CEP-11004. Treatment with a gamma-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated via alpha-secretase processing of APP. In support of these data, overexpression of the Swedish mutant of APP did not inhibit SPARC expression, UV-induced JNK activation and cell death. Our data suggest an important physiological role of APP and alpha-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.

Published
2004

15. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Author

Galluzzi, L, primary, Bravo-San Pedro, J M, additional, Vitale, I, additional, Aaronson, S A, additional, Abrams, J M, additional, Adam, D, additional, Alnemri, E S, additional, Altucci, L, additional, Andrews, D, additional, Annicchiarico-Petruzzelli, M, additional, Baehrecke, E H, additional, Bazan, N G, additional, Bertrand, M J, additional, Bianchi, K, additional, Blagosklonny, M V, additional, Blomgren, K, additional, Borner, C, additional, Bredesen, D E, additional, Brenner, C, additional, Campanella, M, additional, Candi, E, additional, Cecconi, F, additional, Chan, F K, additional, Chandel, N S, additional, Cheng, E H, additional, Chipuk, J E, additional, Cidlowski, J A, additional, Ciechanover, A, additional, Dawson, T M, additional, Dawson, V L, additional, De Laurenzi, V, additional, De Maria, R, additional, Debatin, K-M, additional, Di Daniele, N, additional, Dixit, V M, additional, Dynlacht, B D, additional, El-Deiry, W S, additional, Fimia, G M, additional, Flavell, R A, additional, Fulda, S, additional, Garrido, C, additional, Gougeon, M-L, additional, Green, D R, additional, Gronemeyer, H, additional, Hajnoczky, G, additional, Hardwick, J M, additional, Hengartner, M O, additional, Ichijo, H, additional, Joseph, B, additional, Jost, P J, additional, Kaufmann, T, additional, Kepp, O, additional, Klionsky, D J, additional, Knight, R A, additional, Kumar, S, additional, Lemasters, J J, additional, Levine, B, additional, Linkermann, A, additional, Lipton, S A, additional, Lockshin, R A, additional, López-Otín, C, additional, Lugli, E, additional, Madeo, F, additional, Malorni, W, additional, Marine, J-C, additional, Martin, S J, additional, Martinou, J-C, additional, Medema, J P, additional, Meier, P, additional, Melino, S, additional, Mizushima, N, additional, Moll, U, additional, Muñoz-Pinedo, C, additional, Nuñez, G, additional, Oberst, A, additional, Panaretakis, T, additional, Penninger, J M, additional, Peter, M E, additional, Piacentini, M, additional, Pinton, P, additional, Prehn, J H, additional, Puthalakath, H, additional, Rabinovich, G A, additional, Ravichandran, K S, additional, Rizzuto, R, additional, Rodrigues, C M, additional, Rubinsztein, D C, additional, Rudel, T, additional, Shi, Y, additional, Simon, H-U, additional, Stockwell, B R, additional, Szabadkai, G, additional, Tait, S W, additional, Tang, H L, additional, Tavernarakis, N, additional, Tsujimoto, Y, additional, Vanden Berghe, T, additional, Vandenabeele, P, additional, Villunger, A, additional, Wagner, E F, additional, Walczak, H, additional, White, E, additional, Wood, W G, additional, Yuan, J, additional, Zakeri, Z, additional, Zhivotovsky, B, additional, Melino, G, additional, and Kroemer, G, additional

Published
2014
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21. Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus

Author

Murphy, B M, primary, Engel, T, additional, Paucard, A, additional, Hatazaki, S, additional, Mouri, G, additional, Tanaka, K, additional, Tuffy, L P, additional, Jimenez-Mateos, E M, additional, Woods, I, additional, Dunleavy, M, additional, Bonner, H P, additional, Meller, R, additional, Simon, R P, additional, Strasser, A, additional, Prehn, J H M, additional, and Henshall, D C, additional

Published
2009
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24. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Author

Galluzzi, L, primary, Aaronson, S A, additional, Abrams, J, additional, Alnemri, E S, additional, Andrews, D W, additional, Baehrecke, E H, additional, Bazan, N G, additional, Blagosklonny, M V, additional, Blomgren, K, additional, Borner, C, additional, Bredesen, D E, additional, Brenner, C, additional, Castedo, M, additional, Cidlowski, J A, additional, Ciechanover, A, additional, Cohen, G M, additional, De Laurenzi, V, additional, De Maria, R, additional, Deshmukh, M, additional, Dynlacht, B D, additional, El-Deiry, W S, additional, Flavell, R A, additional, Fulda, S, additional, Garrido, C, additional, Golstein, P, additional, Gougeon, M-L, additional, Green, D R, additional, Gronemeyer, H, additional, Hajnóczky, G, additional, Hardwick, J M, additional, Hengartner, M O, additional, Ichijo, H, additional, Jäättelä, M, additional, Kepp, O, additional, Kimchi, A, additional, Klionsky, D J, additional, Knight, R A, additional, Kornbluth, S, additional, Kumar, S, additional, Levine, B, additional, Lipton, S A, additional, Lugli, E, additional, Madeo, F, additional, Malorni, W, additional, Marine, J-CW, additional, Martin, S J, additional, Medema, J P, additional, Mehlen, P, additional, Melino, G, additional, Moll, U M, additional, Morselli, E, additional, Nagata, S, additional, Nicholson, D W, additional, Nicotera, P, additional, Nuñez, G, additional, Oren, M, additional, Penninger, J, additional, Pervaiz, S, additional, Peter, M E, additional, Piacentini, M, additional, Prehn, J H M, additional, Puthalakath, H, additional, Rabinovich, G A, additional, Rizzuto, R, additional, Rodrigues, C M P, additional, Rubinsztein, D C, additional, Rudel, T, additional, Scorrano, L, additional, Simon, H-U, additional, Steller, H, additional, Tschopp, J, additional, Tsujimoto, Y, additional, Vandenabeele, P, additional, Vitale, I, additional, Vousden, K H, additional, Youle, R J, additional, Yuan, J, additional, Zhivotovsky, B, additional, and Kroemer, G, additional

Published
2009
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26. Role of Smac in cephalostatin-induced cell death

Author

Rudy, A, primary, López-Antón, N, additional, Barth, N, additional, Pettit, G R, additional, Dirsch, V M, additional, Schulze-Osthoff, K, additional, Rehm, M, additional, Prehn, J H M, additional, Vogler, M, additional, Fulda, S, additional, and Vollmar, A M, additional

Published
2008
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28. Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus.

Author

Murphy, B. M., Engel, T., Paucard, A., Hatazaki, S., Mouri, G., Tanaka, K., Tuffy, L. P., Jimenez-Mateos, E. M., Woods, I., Dunleavy, M., Bonner, H. P., Meller, R., Simon, R. P., Strasser, A., Prehn, J. H. M., and Henshall, D. C.

Subjects
HIPPOCAMPUS (Brain), NEOCORTEX, CEREBRAL cortex, LABORATORY mice, PYRROLIDINE
Abstract

Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3-only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed that expression of the BH3-only protein, Bcl-2 interacting mediator of cell death (Bim), increased in the rat hippocampus but not in the neocortex after focal-onset status epilepticus. In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and posttranslational activation of Bim, such as CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Upregulation of bim mRNA was evident after 2 h and Bim protein increased between 4 and 24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared with wild-type animals after seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death after KA treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim-deficient mice was comparable with that in wild-type animals. These results show region-specific differential contributions of Bim to seizure-induced neuronal death. [ABSTRACT FROM AUTHOR]

Published
2010
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29. Single-cell quantification of Bax activation and mathematical modelling suggest pore formation on minimal mitochondrial Bax accumulation.

Author

Düssmann, H., Rehm, M., Concannon, C. G., Anguissola, S., Würstle, M., Kacmar, S., Völler, P., Huber, H. J., and Prehn, J. H. M.

Subjects
APOPTOSIS, MITOCHONDRIA, CELLULAR automata, MITOCHONDRIAL membranes, CELLS
Abstract

Mitochondrial outer membrane permeabilisation (MOMP) during apoptosis is triggered by the activation and oligomerisation of Bax and Bak, but a quantification of these processes in individual cells has not yet been performed. Single-cell imaging of Bax translocation and oligomerisation in Bax-deficient DU-145 cells expressing CFP-Bax and YFP-Bax revealed that both processes started only minutes before or concomitantly with MOMP, with the majority of Bax translocation and oligomerisation occurring downstream of MOMP. Quantification of YFP-Bax concentrations at mitochondria revealed an increase of only 1.8±1.5% at MOMP onset. This was increased to 11.2±3.6% in bak-silenced cells. These data suggested that Bax activation exceeded by far the quantities required for MOMP induction, and that minimal Bax or Bak activation may be sufficient to trigger rapid pore formation. In a cellular automaton modelling approach that incorporated the quantities and movement probabilities of Bax and its inhibitors, activators and enablers in the mitochondrial membrane, we could re-model rapid pore formation kinetics at submaximal Bax activation. [ABSTRACT FROM AUTHOR]

Published
2010
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30. Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway.

Author

Kögel, D., Schomburg, R., Copanaki, E., and Prehn, J. H. M.

Subjects
PROTEIN precursors, AMYLOID, GENE expression, GENETIC regulation, ENZYME inhibitors, EFFECT of radiation on cells
Abstract

The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip® analysis and in vitro kinase assays revealed potent APP-dependent repression of c-Jun, its target gene SPARC and reduced basal c-Jun N-terminal kinase (JNK) activity in PC12 cells overexpressing APP. UV-induced activation of the JNK signalling pathway and subsequent apoptosis were likewise reduced by APP and this effect could be mimicked by the indirect JNK inhibitor CEP-11004. Treatment with a?-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated viaa-secretase processing of APP. In support of these data, overexpression of the Swedish mutant of APP did not inhibit SPARC expression, UV-induced JNK activation and cell death. Our data suggest an important physiological role of APP anda-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.Cell Death and Differentiation (2005) 12, 1-9. doi:10.1038/sj.cdd.4401495 [ABSTRACT FROM AUTHOR]

Published
2005
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31. Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration.

Author

Behan, Á T, Breen, B, Hogg, M, Woods, I, Coughlan, K, Mitchem, M, and Prehn, J H M

Subjects
JOURNALISTIC errors, ACID-sensing ion channels, NEURODEGENERATION
Abstract

The article presents a retraction for the article "Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration," by Á. T. Behan and colleagues that was published online in the November 1, 2013 issue.

Published
2014
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