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Saura-Esteller J

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BEC 2020.1 Mitochondrial physiology
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COST Action CA15203 (2016-2021): MitoEAGLE
Evolution-Age-Gender-Lifestyle-Environment: mitochondrial fitness mapping

Saura-Esteller J

MitoPedia topics: EAGLE 

COST: Member

Name Saura-Esteller José,
Institution University of Barcelona
Address Gran Via de les Corts Catalanes, 585, 08007
City Barcelona
Country Spain
Email [email protected]
O2k-Network Lab



Saura-Esteller 2021 Int J Mol Sci2021Saura-Esteller J, Sánchez-Vera I, Núñez-Vázquez S, Cosialls AM, Gama-Pérez P, Bhosale G, Mendive-Tapia L, Lavilla R, Pons G, Garcia-Roves PM, Duchen MR, Iglesias-Serret D, Gil J (2021) Activation of the integrated stress response and ER stress protect from fluorizoline-induced apoptosis in HEK293T and U2OS cell lines. Int J Mol Sci 22:6117.


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MitoEAGLE Short-Term Scientific Mission

Work Plan summary
Dear Sir/Madam: My name is Jose Saura Esteller, I am a third year PhD Student in the Biomedicine program at the University of Barcelona and I am developing my thesis under the supervision of Dr. Joan Gil. The research of our group is centered on fluorizoline, a novel synthetic compound that binds to mitochondrial proteins Prohibitins and ultimately induces apoptosis. More precisely, we are interested in investigating how the binding of fluorizoline to Prohibitin in the mitochondria alters mitochondrial physiology and which are the molecular pathways involved in the induction of apoptosis by fluorizoline.
I am applying for this Short Term Scientific Mission with the aim of stablishing a collaboration with Prof. Michael Duchen’s group at the University College in London that, as our own group, belongs to MitoEagle network. We have decided to contact Prof. Duchen because of his remarkable expertise in the fields of mitochondrial pathophysiology, calcium homeostasis and cell signaling. Prof. Duchen’s scientific background and available facilities could not be more appropriate for the selected objectives of this stay, as he has at his disposal all the required instruments to perform measures of mitochondrial membrane potential, oxygen consumption, calcium concentration determination and mitochondrial visualization. The results obtained during this stay would be included in my doctoral thesis and could be crucial to understand the mechanism of action of fluorizoline and therefore to find a suitable clinical application for this synthetic drug. I am sure that this will be an excellent opportunity to strengthen my working abilities and to get in touch with other researchers, which surely will help me to notice and to take in consideration different points of view about science in general and about our research project in particular.
Thank you for the opportunity of applying to this STSM grant and hope to hear soon from you! Jose.
1. Aim & motivation - Please explain the scientific and/or other motivation for the STSM and what scientific and/or other outcomes you aim to accomplish with the STSM.
Our group has discovered a new family of pro-apoptotic compounds, fluorinated thiazolines, which display promising characteristics for cancer treatment (Perez-Perarnau A, et al. 2014). Among this family of compounds, we selected fluorizoline due to its higher activity. Fluorizoline induces apoptosis in a wide range of tumor cell lines with doses in the low micromolar range. Importantly, non- malignant cells lines are more resistant to fluorizoline treatment than tumour cell lines. These results have been already confirmed using primary cells from hematologic malignancies (Pomares H, et al. 2016; Cosialls AM, et al. 2017). We have recently identied and validated the mitochondrial proteins Prohibitin 1 and Prohibitin 2 as the molecular targets for fluorizoline and have demonstrated their requirement for fluorizoline-induced apoptosis (Perez-Perarnau A, et al. 2014; Moncunill- Massaguer C, et al. 2015) The main aim of the STSM is to analyze the direct effect of the interaction of fluorizoline with the mitochondrial protein Prohibitin. Prohibitins are key proteins in the organization of the inner mitochondrial membrane (IMM) and mitochondrial cristae which have been related to various processes occurring in the IMM e.g. regulation of the proteolysis of membrane proteins, control of the assembly of subunits of the Oxidative phosphorylation (OXPHOS) machinery or control of mitochondrial structure and function through the regulation of the proteolytic cleavage of OPA1. Thus, it is conceivable that fluorizoline alters mitochondrial function through its interaction with Prohibitin. In this STSM we plan to analyze OXPHOS activity, membrane potential, mitochondrial structure, mitochondrial and cytosolic calcium concentration and ATP concentration both in isolated mitochondria and intact cells. With these experiments, we seek to obtain more information of the mechanism of action of fluorizoline.
2. Proposed contribution to the scientific objectives of the Action.
In this STSM request, we propose to start a collaboration between the group led by Prof. MR Duchen at the University College in London and our own group, both of which belong to the MitoEagle Network. Through this collaboration, we expect to obtain new insight in the mechanism of action of a new synthetic drug with pro-apoptotic activity. Evidence obtained in the proposed experiments could help to stablish the application of fluorizoline as a cancer therapy. In addition, fluorizoline is the first synthetic molecule reported to directly bind to prohibitins. Prohibitin functions in the IMM are not fully understood, therefore fluorizoline may represent an invaluable research tool to explore processes that involve Prohibitin.
3. Techniques - Please detail what techniques or equipment you may learn to use, if applicable.
To achieve the objectives proposed in this STSM the solicitant will perform new techniques and use new equipment: In the first place, isolated mitochondria will be obtained from rat liver as described in Briston T, et al., 2016. Secondly, OXPHOS activity will be determined through oxygen consumption analysis using the Oroboros Oxygraph-2K system on isolated mitochondria or cells in suspension. Seahorse equipment may also be used for adherernt cells if necessary. We will compare impacto of fluoriozline on all major parameters of mitochondrial respiration in otder to stablish its site of action. Finally, mitochondrial calcium retention capacity will be determined using fluorescent dyes and the FLIPRTETRA technology for the simultaneous detection of calcium concentration at real-time in multi-well plates on isolated mitochondria as described in Briston T, et al., 2017. Additionally, fluorescent dyes and confocal microscopy will be used to study modulations on mitochondrial or cytosolic calcium concentration on intact cells.
4. Planning - Please detail the steps you will take to achieve your proposed aim.
The current working hypothesis of our group suggests that fluorizoline through its binding to mitochondrial Prohibitins alters mitochondrial form and function activating stress pathways and finally inducing apoptosis.
Consequently, the objectives proposed for this stay are focused on the characterization of mitochondrial function upon fluorizoline treatment:
Objetive 1. Analysis of proteolytic cleavage of L-OPA1 by fluorizoline on isolated mitochondria.
Objetive 2. OXPHOS and IMM membrane potential measurement in presence of fluorizoline on isolated mitochondria and intact cells.
Objective 3. Cytosolic and mitochondrial Calcium concentration determination on tumour cell lines upon treatment with fluorizoline.
Objective 4. ATP concentration determination upon fluorizoline treatment.
Working Schedule: Objetive 1st Month 2nd Month 3rd
Month 1 X 2 X X 3 X X 4 X
References: Briston T, Lewis S, Koglin M, Mistry K, Shen Y, Hartopp N, Katsumata R, Fukumoto H, Duchen MR, Szabadkai G, Staddon JM, Roberts M, Powney B. Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria.
  • Sci Rep. 2016 Nov 25;6:37798. doi: 10.1038/srep37798. Briston T, Roberts M, Lewis S, Powney B, M Staddon J, Szabadkai G, Duchen MR. Mitochondrial permeability transition pore: sensitivity to opening and mechanistic dependence on substrate availability.
  • Sci Rep. 2017 Sep 5;7(1):10492. doi: 10.1038/s41598-017-10673-8. Cosialls AM, Pomares H, Iglesias-Serret D, Saura-Esteller J, Nunez-Vazquez S, Gonzalez-Girones DM, de la Banda E, Preciado S, Albericio F, Lavilla R, Pons G, Gonzalez-Barca EM, Gil J. The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax.
  • Haematologica. 2017 Sep;102(9):1587-1593. doi: 10.3324/haematol.2016.162958. Epub 2017 Jun 15. Moncunill- Massaguer C, Saura-Esteller J, Perez-Perarnau A, Palmeri CM, Nunez-Vazquez S, Cosialls AM, Gonzalez-Girones DM, Pomares H, Korwitz A, Preciado S, Albericio F, Lavilla R, Pons G, Langer T, Iglesias-Serret D, Gil J. A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation.
  • Oncotarget. 2015 Dec 8;6(39):41750-65. doi: 10.18632/oncotarget.6154. Perez-Perarnau A, Preciado S, Palmeri CM, Moncunill-Massaguer C, Iglesias-Serret D, Gonzalez-Girones DM, Miguel M, Karasawa S, Sakamoto S, Cosialls AM, Rubio-Patino C, Saura-Esteller J, Ramon R, Caja L, Fabregat I, Pons G, Handa H, Albericio F, Gil J, Lavilla R. A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins..
  • Angew Chem Int Ed Engl. 2014 Sep 15;53(38):10150-4. doi: 10.1002/anie.201405758. Pomares H, Palmeri CM, Iglesias-Serret D, Moncunill- Massaguer C, Saura-Esteller J, Nunez-Vazquez S, Gamundi E, Arnan M, Preciado S, Albericio F, Lavilla R, Pons G, Gonzalez-Barca EM, Cosialls AM, Gil J. Targeting prohibitins induces apoptosis in acute myeloid leukemia cells.
  • Oncotarget. 2016 Oct 4;7(40):64987-65000. doi: 10.18632/oncotarget.11333.