Head of the team "Metabolic plasticity in health and disease"
Our team is studying the role of mitochondria in the metabolic plasticity of cancer cells with the aim of discovering new biomarkers and proposing new therapeutic strategies that could improve the tumour response to cancer treatments. Indeed, mitochondria, which are energy production factories in the cell, play an important role in tumorigenesis and the response of tumour cells to anticancer treatments.
Metabolic plasticity is a fundamental ability that allows cells to adapt their metabolic status to specific needs during proliferation, differentiation, activation in response to various stimuli or in response to stress conditions. In this context, mitochondria, which are major players through their contribution to metabolism, communicate with other cellular compartments, particularly with the nucleus. Thus, mitochondrial activity is finely regulated through a bidirectional dialogue with the nucleus. In the first place, an anterograde dialogue (from the nucleus to mitochondria) controls the mitochondrial biogenesis by allowing the import of 1000 to 1500 proteins into one of the four sub-compartments of the organelle, namely the inner and outer membranes, the mitochondrial matrix and the intermembrane space. In return, through the production of ATP and other metabolites, mitochondria establish a retrograde dialogue with the nucleus (from mitochondria to the nucleus), which impacts on the expression of genes necessary for, among other things, cellular metabolic programs and secretion activities involved in systemic pathways.
We are developing an integrative research program for a better understanding of the mitochondrio-nuclear dialogue mentioned above. Our work will focus on the mitochondrial import pathway AIF/CHCHD4, which regulates the import of a family of proteins involved in cell survival, adaptation to stress and response to apoptotic stimuli. Our objectives will be 1/ to better understand the role of these proteins in the metabolic plasticity of normal and tumour cells and 2/ to exploit the acquired knowledge for the generation of new molecular tools, the discovery of new biomarkers and the proposal of new therapeutic targets and anti-cancer molecules to be combined with conventional therapeutic strategies (radio- or chemotherapy).
This research program is developed within 3 axes:
Axis n°1: Molecular characterization of the AIF/CHCHD4 complex. In order to characterize the AIF/CHCHD4 complex, we are aiming to understand signaling pathways that regulate this complex, to generate tools to target mitochondria and study the interaction between AIF/CHCHD4, and to identify, through high-throughput screening, molecules that could modulate the AIF/CHCHD4 import pathway and thus affect metabolism, cancer cell fate and stress signaling response.
Axis n°2: Impact of the AIF/CHCHD4 pathway on tumour metabolism. Since mitochondria are now recognized as key players in the metabolic plasticity of various cancer cells and in the sensing and propagation of signals generated either by tumor cells or by the tumor microenvironment, within this axis, through genetic and pharmacological manipulations, we are studying the role of the AIF/CHCHD4 pathway in tumor metabolism, tumorigenesis, response to therapeutic agents and resistance to anticancer treatments.
Axis n°3: Metabolic bases of stem cell differentiation. Metabolic plasticity is fundamental for the control of stem cell homeostasis and the regulation of their ability to differentiate into specific cell lineages. In this axis, we 1/ study the regulation of the AIF/CHCHD4 import pathway during stem cell differentiation and 2/ evaluate its impact on the ability of mitochondria to adapt their activity to the metabolic and bioenergetic needs of stem cells that undergo differentiation.
Historically, the team hosts one of the axes of the former UMR 8203 (2011-2019) led by Lluis M. Mir. More precisely, following the work carried out over three decades, an activity centered on the study of the interactions of electric and electromagnetic fields is being pursued. The aim is to modify the permeability of cell membranes and organelles, to exploit all the resulting applications (electrochemotherapy, non-viral gene therapy, irreversible electroporation in oncology, etc.) and to study the bases and fundamental mechanisms.
Our laboratory is equipped with a Seahorse analyzer (Seahorse, Agilent), which allows simultaneous and real-time measurement of the cell’s main energy pathways. Our work is backed up by the platforms managed by Gustave Roussy’s UMS AMMICA (UMS 3655) as well as the CIBLOT high throughput screening platform, labeled IBISA, which is part of Criblage@ParisSaclay and Chembiofrance’s national infrastructure.
Head of the UMR9018 METSY unit
Technical manager of the Seahorse platform of UMR9018
Technical manager of the cytometry platform
Franck M ANDRÉ
Lluis M MIR
Post Doc CNRS
Post Doc CNRS
Post Doc CNRS
PhD student UP SACLAY
Hong Toan LAI
PhD student CNRS
PhD student CNRS
PhD student UP SACLAY
González-Cuevas JA, Argüello R, Florentin M, André FM, Mir LM. Experimental and Theoretical Brownian Dynamics Analysis of Ion Transport During Cellular Electroporation of E. coli Bacteria. Ann Biomed Eng. 2023 Aug 31. doi: 10.1007/s10439-023-03353-4.
Tran BT, Gelin A, Durand S, Texier M, Daste A, Toullec C, Benihoud K, Breuskin I, Gorphe P, Garic F, Brenner C, Le Tourneau C, Fayette J, Niki T, David M, Busson P, Even C. Plasma galectins and metabolites in advanced head and neck carcinomas: evidence of distinct immune characteristics linked to hypopharyngeal tumors. Oncoimmunology. 2022 Dec 17;12(1):2150472. doi: 10.1080/2162402X.2022.2150472.
Nedara K, Reinhardt C, Lebraud E, Arena G, Gracia C, Buard V, Pioche-Durieu C, Castelli F, Colsch B, Bénit P, Rustin P, Albaud B, Gestraud P, Baulande S, Servant N, Deutsch E, Verbavatz JM, Brenner C, Milliat F, Modjtahedi N. Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation. Front Oncol. 2022 Oct 31;12:958155. doi: 10.3389/fonc.2022.958155.
Merla C, Nardoni M, Scherman M, Petralito S, Caramazza L, Apollonio F, Liberti M, Paolicelli P, Attal-Tretout B, Mir LM. Changes in hydration of liposome membranes exposed to nanosecond electric pulses detected by wide-field Coherent anti-Stokes Raman microspectroscopy. Bioelectrochemistry. 2022 Oct;147:108218. doi: 10.1016/j.bioelechem.2022.108218.
Lai HT, Naumova N, Marchais A, Gaspar N, Geoerger B, Brenner C. Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma. Front Cell Dev Biol. 2022 Aug 22;10:948097. doi: 10.3389/fcell.2022.948097.
Tellado M, Mir LM, Maglietti F. Veterinary Guidelines for Electrochemotherapy of Superficial Tumors. Front Vet Sci. 2022 Jul 27;9:868989. doi: 10.3389/fvets.2022.868989.
Ichim G, Gibert B, Adriouch S, Brenner C, Davoust N, Desagher S, Devos D, Dokudovskaya S, Dubrez L, Estaquier J, Gillet G, Guénal I, Juin PP, Kroemer G, Legembre P, Levayer R, Manon S, Mehlen P, Meurette O, Micheau O, Mignotte B, Nguyen-Khac F, Popgeorgiev N, Poyet JL, Priault M, Ricci JE, Riquet FB, Susin SA, Suzanne M, Vacher P, Walter L, Mollereau B. Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network. Biomolecules. 2022 Jun 28;12(7):901. doi: 10.3390/biom12070901.
Lai HT, Canoy RJ, Campanella M, Vassetzky Y, Brenner C. Ca2+ Transportome and the Interorganelle Communication in Hepatocellular Carcinoma. Cells. 2022 Feb 26;11(5):815. doi: 10.3390/cells11050815.
Liu D, Peyre F, Loissell-Baltazar YA, Courilleau D, Lacas-Gervais S, Nicolas V, Jacquet E, Dokudovskaya S, Taran F, Cintrat JC, Brenner C. Identification of Small Molecules Inhibiting Cardiomyocyte Necrosis and Apoptosis by Autophagy Induction and Metabolism Reprogramming. Cells. 2022 Jan 29;11(3):474. doi: 10.3390/cells11030474.
Consales C, Merla C, Benassi B, Garcia-Sanchez T, Muscat A, André FM, Marino C, Mir LM. Biological effects of ultrashort electric pulses in a neuroblastoma cell line: the energy density role. Int J Radiat Biol. 2022;98(1):109-121. doi: 10.1080/09553002.2022.1998704.
Arena G, Modjtahedi N, Kruger R. Exploring the contribution of the mitochondrial disulfide relay system to Parkinson’s disease: the PINK1/CHCHD4 interplay. Neural Regen Res. 2021 Nov;16(11):2222-2224. doi: 10.4103/1673-5374.310679.
Tesse A, André FM, Ragot T. Aluminum particles generated during millisecond electric pulse application enhance adenovirus-mediated gene transfer in L929 cells. Sci Rep. 2021 Sep 6;11(1):17725. doi: 10.1038/s41598-021-96781-y.
Gailliègue FN, Tamošiūnas M, André FM, Mir LM. A Setup for Microscopic Studies of Ultrasounds Effects on Microliters Scale Samples: Analytical, Numerical and Experimental Characterization. Pharmaceutics. 2021 Jun 8;13(6):847. doi: 10.3390/pharmaceutics13060847.
Dickson-Murray E, Nedara K, Modjtahedi N, Tokatlidis K. The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space. Antioxidants (Basel). 2021 Apr 12;10(4):592. doi: 10.3390/antiox10040592.
Liu D, Lai HT, Peyre F, Brenner C. Multiple analysis of mitochondrial metabolism, autophagy and cell death. Methods Cell Biol. 2021;164:95-112. doi: 10.1016/bs.mcb.2021.02.001.
Boutary S, Caillaud M, El Madani M, Vallat JM, Loisel-Duwattez J, Rouyer A, Richard L, Gracia C, Urbinati G, Desmaële D, Echaniz-Laguna A, Adams D, Couvreur P, Schumacher M, Massaad C, Massaad-Massade L. Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A. Commun Biol. 2021 Mar 9;4(1):317. doi: 10.1038/s42003-021-01839-2.
Ghorbel A, André FM, Mir LM, García-Sánchez T. Electrophoresis-assisted accumulation of conductive nanoparticles for the enhancement of cell electropermeabilization. Bioelectrochemistry. 2021 Feb;137:107642. doi: 10.1016/j.bioelechem.2020.107642.
Meyenberg Cunha-de Padua M, Fabbri L, Dufies M, Lacas-Gervais S, Contenti J, Voyton C, Fazio S, Irondelle M, Mograbi B, Rouleau M, Sadaghianloo N, Rovini A, Brenner C, Craigen WJ, Bourgeais J, Herault O, Bost F, Mazure NM. Evidences of a Direct Relationship between Cellular Fuel Supply and Ciliogenesis Regulated by Hypoxic VDAC1-ΔC. Cancers (Basel). 2020 Nov 23;12(11):3484. doi: 10.3390/cancers12113484.
Reinhardt C, Arena G, Nedara K, Edwards R, Brenner C, Tokatlidis K, Modjtahedi N. AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway. Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165746. doi: 10.1016/j.bbadis.2020.165746.
Pervaiz S, Bellot GL, Lemoine A, Brenner C. Redox signaling in the pathogenesis of human disease and the regulatory role of autophagy. Int Rev Cell Mol Biol. 2020;352:189-214. doi: 10.1016/bs.ircmb.2020.03.002.
Rao S, Mondragón L, Pranjic B, Hanada T, Stoll G, Köcher T, Zhang P, Jais A, Lercher A, Bergthaler A, Schramek D, Haigh K, Sica V, Leduc M, Modjtahedi N, Pai TP, Onji M, Uribesalgo I, Hanada R, Kozieradzki I, Koglgruber R, Cronin SJ, She Z, Quehenberger F, Popper H, Kenner L, Haigh JJ, Kepp O, Rak M, Cai K, Kroemer G, Penninger JM. AIF-regulated oxidative phosphorylation supports lung cancer development. Cell Res. 2019 Jul;29(7):579-591. doi: 10.1038/s41422-019-0181-4.