Go to the content. | Move to the navigation | Go to the site search | Go to the menu | Contacts | Accessibility

| Create Account

Pellattiero, Anna (2019) Pharmacological modulation of mitochondrial dynamics: identification of a specific OPA1 inhibitor to enhance apoptotic release of cytochrome c. [Ph.D. thesis]

Full text disponibile come:

[img]PDF Document
Thesis not accessible until 16 January 2022 for intellectual property related reasons.
Visibile to: nobody

11Mb

Abstract (italian or english)

The GTPase activity of OPA1, a dynamin-related mitochondrial protein upregulated in several tumors, controls cristae remodeling, cytochrome c release and apoptosis. To pharmacologically target OPA1 in cancer, we setup and iterated a high-throughput screening of a diversity based chemical library of 10,000 drug-like small molecules for recombinant purified OPA1 GTPase activity inhibition, identifying 8 candidates that were confirmed in a secondary screen. The most promising hit (MYLS22) was highly specific, as it could bind to recombinant OPA1 GTPase and did not inhibit recombinant Dynamin 1 GTPase activity. MYLS22 was not mitochondriotoxic, but it increased OPA1 oligomers disassembly and cytochrome c release in response to the proapoptotic stimulus BID in purified mitochondria and to hydrogen peroxide in cells, where MYLS22 caused the expected mitochondrial fragmentation. MYLS22 also phenocopied the inhibition of breast cancer cells migration caused by OPA1 silencing. Thus, we identified a first-in-kind OPA1 inhibitor with potential anti-cancer properties.


EPrint type:Ph.D. thesis
Tutor:Scorrano, Luca
Ph.D. course:Ciclo 30 > Corsi 30 > BIOSCIENZE
Data di deposito della tesi:15 January 2019
Anno di Pubblicazione:15 January 2019
Key Words:OPA1, small molecule, apoptosis, mitochondria, mitochondrial dynamics
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:11624
Depositato il:07 Nov 2019 14:50
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

Anderson, G.R., Wardell, S.E., Cakir, M., Yip, C., Ahn, Y.R., Ali, M., Yllanes, A.P., Chao, C.A., McDonnell, D.P., and Wood, K.C. (2018). Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nat Commun 9, 1677. Cerca con Google

Bordt, E.A.e.a. (2017). The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species: Developmental Cell. Dev Cell. Cerca con Google

Bunnage, M.E., Chekler, E.L., and Jones, L.H. (2013). Target validation using chemical probes. Nat Chem Biol 9, 195-199. Cerca con Google

Cassidy-Stone, A., Chipuk, J.E., Ingerman, E., Song, C., Yoo, C., Kuwana, T., Kurth, M.J., Shaw, J.T., Hinshaw, J.E., Green, D.R., et al. (2008). Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14, 193-204. Cerca con Google

Chen, H., Chomyn, A., and Chan, D.C. (2005). Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280, 26185-26192. Cerca con Google

Cipolat, S., Martins de Brito, O., Dal Zilio, B., and Scorrano, L. (2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 101, 15927- 15932. Cerca con Google

Cogliati, S., Frezza, C., Soriano, M.E., Varanita, T., Quintana-Cabrera, R., Corrado, M., Cipolat, S., Costa, V., Casarin, A., Gomes, L.C., et al. (2013). Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155, 160-171. Cerca con Google

Copeland, R.A. (2003). Mechanistic considerations in high-throughput screening. Analytical Biochemistry 320, 1-12. Cerca con Google

Danial, N.N., Gramm, C.F., Scorrano, L., Zhang, C.Y., Krauss, S., Ranger, A.M., Datta, S.R., Greenberg, M.E., Licklider, L.J., Lowell, B.B., et al. (2003). BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952-956. Cerca con Google

Daumke, O., and Praefcke, G.J. (2016). Invited review: Mechanisms of GTP hydrolysis and conformational transitions in the dynamin superfamily. Biopolymers 105, 580-593. Cerca con Google

Del Dotto, V., Mishra, P., Vidoni, S., Fogazza, M., Maresca, A., Caporali, L., McCaffery, J.M., Cappelletti, M., Baruffini, E., Lenaers, G., et al. (2017). OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions. Cell Rep 19, 2557-2571. Cerca con Google

Fang, H.Y., Chen, C.Y., Chiou, S.H., Wang, Y.T., Lin, T.Y., Chang, H.W., Chiang, I.P., Lan, K.J., and Chow, K.C. (2012). Overexpression of optic atrophy 1 protein increases cisplatin resistance via inactivation of caspase-dependent apoptosis in lung adenocarcinoma cells. Hum Pathol 43, 105-114. Cerca con Google

Ford, M.G., Jenni, S., and Nunnari, J. (2011). The crystal structure of dynamin. Nature 477, 561-566. Cerca con Google

Franco, A., Kitsis, R.N., Fleischer, J.A., Gavathiotis, E., Kornfeld, O.S., Gong, G., Biris, N., Benz, A., Qvit, N., Donnelly, S.K., et al. (2016). Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature 540, 74-79. Cerca con Google

Frezza, C., Cipolat, S., Martins, d.B., Micaroni, M., Beznoussenko, G.V., Rudka, T., Bartoli, D., Polishuck, R.S., Danial, N.N., De Strooper, B., et al. (2006). OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion. Cell 126, 177-189. Cerca con Google

Frezza, C., Cipolat, S., and Scorrano, L. (2007). Measuring mitochondrial shape changes and their consequences on mitochondrial involvement during apoptosis. Methods Mol Biol 372, 405-420. Cerca con Google

Fulda, S., Galluzzi, L., and Kroemer, G. (2010). Targeting mitochondria for cancer therapy. Nature Reviews Drug Discovery 9, 447-464. Cerca con Google

Goktug, A.N., Chai, S.C., and Chen, T. (2013). Data Analysis Approaches in High Throughput Screening. Cerca con Google

Green, D.R., and Kroemer, G. (2004). The pathophysiology of mitochondrial cell death. Science 305, 626-629. Cerca con Google

Griparic, L., van der Wel, N.N., Orozco, I.J., Peters, P.J., and van der Bliek, A.M. (2004). Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem 279, 18792- 18798. Cerca con Google

Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646-674. Cerca con Google

Hann, M.M., and Simpson, G.L. (2014). Intracellular drug concentration and disposition--the missing link? Methods 68, 283-285. Cerca con Google

Irwin, W.A., Bergamin, N., Sabatelli, P., Reggiani, C., Megighian, A., Merlini, L., Braghetta, P., Columbaro, M., Volpin, D., Bressan, G.M., et al. (2003). Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 35, 367-371. Cerca con Google

Kaur, M., Reed, E., Sartor, O., Dahut, W., and Figg, W.D. (2002). Suramin's development: what did we learn? Invest New Drugs 20, 209-219. Cerca con Google

Kelley, L.A., Mezulis, S., Yates, C.M., Wass, M.N., and Sternberg, M.J. (2015). The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10, 845- 858. Cerca con Google

Kong, B., Wang, Q., Fung, E., Xue, K., and Tsang, B.K. (2014). p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is Cerca con Google

mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. J Biol Chem 289, 27134-27145. Cerca con Google

Landes, T., Emorine, L.J., Courilleau, D., Rojo, M., Belenguer, P., and Arnaune- Pelloquin, L. (2010). The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms. EMBO Rep 11, 459-465. Cerca con Google

Lee, Y.J., Jeong, S.Y., Karbowski, M., Smith, C.L., and Youle, R.J. (2004). Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15, 5001-5011. Cerca con Google

Leonard, M., Doo Song, B., Ramachandran, R., and Schmid, S.L. (2005). Robust Colorimetric Assays for Dynamin's Basal and Stimulated GTPase Activities. In Methods in Enzymology (Academic Press), pp. 490-503. Cerca con Google

Li, L., Thomas, R.M., Suzuki, H., De Brabander, J.K., Wang, X., and Harran, P.G. (2004). A small molecule Smac mimic potentiates TRAIL- and TNFalpha-mediated cell death. Science 305, 1471-1474. Cerca con Google

Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46, 3-26. Cerca con Google

Lopez, J., and Tait, S.W. (2015). Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer 112, 957-962. Cerca con Google

Meric-Bernstam, F., and Mills, B.G. (2012). Overcoming implementation challenges of personalized cancer therapy. Nature Reviews Clinical Oncology 9, 542. Cerca con Google

Morgan, P., Van Der Graaf, P.H., Arrowsmith, J., Feltner, D.E., Drummond, K.S., Wegner, C.D., and Street, S.D. (2012). Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today 17, 419-424. Cerca con Google

Olichon, A., Baricault, L., Gas, N., Guillou, E., Valette, A., Belenguer, P., and Lenaers, G. (2003). Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278, 7743-7746. Cerca con Google

Olichon, A., Landes, T., Arnaune-Pelloquin, L., Emorine, L.J., Mils, V., Guichet, A., Delettre, C., Hamel, C., Amati-Bonneau, P., Bonneau, D., et al. (2007). Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis. J Cell Physiol 211, 423-430. Cerca con Google

Orrenius, S., Gogvadze, V., and Zhivotovsky, B. (2007). Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47, 143-183. Cerca con Google

Patten, D.A., Wong, J., Khacho, M., Soubannier, V., Mailloux, R.J., Pilon-Larose, K., MacLaurin, J.G., Park, D.S., McBride, H.M., Trinkle-Mulcahy, L., et al. (2014). OPA1- dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J 33, 2676-2691. Cerca con Google

Petronilli, V., Penzo, D., Scorrano, L., Bernardi, P., and Di Lisa, F. (2001). The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem 276, 12030-12034. Cerca con Google

Quintana-Cabrera, R., Quirin, C., Glytsou, C., Corrado, M., Urbani, A., Pellattiero, A., Calvo, E., Vazquez, J., Enriquez, J.A., Gerle, C., et al. (2018). The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function. Nature communications 9, 3399. Cerca con Google

Rizzuto, R., Bernardi, P., and Pozzan, T. (2000). Mitochondria as all-round players of the calcium game. J Physiol 529 Pt 1, 37-47. Cerca con Google

Rocha, A.G., Franco, A., Krezel, A.M., Rumsey, J.M., Alberti, J.M., Knight, W.C., Biris, N., Zacharioudakis, E., Janetka, J.W., Baloh, R.H., et al. (2018). MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A. Science 360, 336-341. Cerca con Google

Rossignol, R., Gilkerson, R., Aggeler, R., Yamagata, K., Remington, S.J., and Capaldi, R.A. (2004). Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64, 985-993. Cerca con Google

Sato, S.-i., Murata, A., Orihara, T., Shirakawa, T., Suenaga, K., Kigoshi, H., and Uesugi, M. (2011). Marine Natural Product Aurilide Activates the OPA1-Mediated Apoptosis by Binding to Prohibitin. Chemistry & Biology 18, 131-139. Cerca con Google

Scorrano, L. (2009). Opening the doors to cytochrome c: changes in mitochondrial shape and apoptosis. Int J Biochem Cell Biol 41, 1875-1883. Cerca con Google

Scorrano, L., Ashiya, M., Buttle, K., Weiler, S., Oakes, S.A., Mannella, C.A., and Korsmeyer, S.J. (2002). A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2, 55-67. Cerca con Google

Scorrano, L., and Korsmeyer, S.J. (2003). Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304, 437-444. Cerca con Google

Scorrano, L., Oakes, S.A., Opferman, J.T., Cheng, E.H., Sorcinelli, M.D., Pozzan, T., and Korsmeyer, S.J. (2003). BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135-139. Cerca con Google

Song, Z., Chen, H., Fiket, M., Alexander, C., and Chan, D.C. (2007). OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 178, 749-755. Cerca con Google

Teuscher, K.B., Zhang, M., and Ji, H. (2017). A Versatile Method to Determine the Cellular Bioavailability of Small-Molecule Inhibitors. Cerca con Google

Varanita, T., Soriano, M.E., Romanello, V., Zaglia, T., Quintana-Cabrera, R., Semenzato, M., Menabo, R., Costa, V., Civiletto, G., Pesce, P., et al. (2015). The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab 21, 834-844. Cerca con Google

Wallace, D.C. (2005). A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39, 359-407. Cerca con Google

Wee, Y., Liu, Y., Lu, J., Li, X., and Zhao, M. (2018). Identification of novel prognosis- related genes associated with cancer using integrative network analysis. Sci Rep 8, 3233. Cerca con Google

Yamaguchi, R., Lartigue, L., Perkins, G., Scott, R.T., Dixit, A., Kushnareva, Y., Kuwana, T., Ellisman, M.H., and Newmeyer, D.D. (2008). Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Mol Cell 31, 557-569. Cerca con Google

Zhang, X.D. (2007). A pair of new statistical parameters for quality control in RNA interference high-throughput screening assays. Genomics 89, 552-561. Cerca con Google

Zhao, J., Zhang, J., Yu, M., Xie, Y., Huang, Y., Wolff, D.W., Abel, P.W., and Tu, Y. (2012). Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 32, 4814. Cerca con Google

Zhao, X., Tian, C., Puszyk, W.M., Ogunwobi, O.O., Cao, M., Wang, T., Cabrera, R., Nelson, D.R., and Cerca con Google

Liu, C. (2013). OPA1 downregulation is involved in sorafenib- induced apoptosis in hepatocellular carcinoma. Lab Invest 93, 8-19. Cerca con Google

Solo per lo Staff dell Archivio: Modifica questo record