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    Team : Mitochondria, bioenergetics, metabolism and signaling

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    Team leaders :

     

    Our team is involved in the bioenergetics role of mitochondria, which has multiple facets. Apart from adaptive modulation of the oxidative phosphorylation pathway itself, the mitochondria are able to modify rate of oxidation and routing of the different energetic substrates. The different projects developed in the team aim at elucidating how and why these responses take place and what are their consequences for the cell and organism.

     

    Objectives

     

    The aim of the team is to study the crosstalk between mitochondrial bioenergetics and the rest of the cell with its impact on tissue and organism. Two different situations are encountered. Cellular bioenergetics can be primarily targeted, either by genetic defects or environmental insult; in that case we analyze the extent of deleterious consequences and potential compensatory responses. Conversely, cellular bioenergetics can often be modulated in pathological states (over-nutrition, obesity, diabetes, cancer…); in that case the question resides in their adaptive / causative / aggravating role in the disease state. Improving the knowledge of mitochondrial bioenergetics within these different situations aims to define where and how mitochondria constitute a determining factor for a complex phenotype.

    The aims of our ongoing studies are:

    - Among the pathophysiological consequences of primary genetic oxidative phosphorylation (OXPHOS) defect, some totally unexpected ones reaching far beyond the mitochondrial compartment have been observed (Auré et al 2013). The molecular events underlying these unexpected phenotypes are presently analyzed.

    - Mitochondrial oxidation of hydrogen sulfide (H2S), entering electrons at the quinone level in the respiratory chain, represents a specific and previously ignored / overlooked bioenergetic mechanism, which has consequences on hypoxia sensing and might underlie part of that gas-transmitter signaling.

    - Through the role of UCP2, a mitochondrial transporter, we discuss the impact of the mitochondrial regulation of the balance between glycolysis and oxidative metabolism on cell proliferation and cancer development.

     

    Main publications

     

    Haouzi P, Gueguinou M, Sonobe T, Judenherc-Haouzi A, Tubbs N, Trebak M, Cheung J, Bouillaud F. Revisiting the physiological effects of methylene blue as a treatment of cyanide intoxication. Clin Toxicol (Phila). 2018 Feb 16:1-13.

    Broche B, Ben Fradj S, Aguilar E, Sancerni T, Bénard M, Makaci F, Berthault C, Scharfmann R, Alves-Guerra MC*, Duvillié B*. Mitochondrial Protein UCP2 Controls Pancreas Development. Diabetes. 2018 Jan;67(1):78-84. *corresponding author

    Lorenz C#, Lesimple P#, Bukowiecki R, Zink A, Inak G, Mlody B, Singh M, Semtner  M, Mah N, Auré K, Leong M, Zabiegalov O, Lyras EM, Pfiffer V, Fauler B, Eichhorst J, Wiesner B, Huebner N, Priller J, Mielke T, Meierhofer D, Izsvák Z, Meier JC, Bouillaud F, Adjaye J, Schuelke M, Wanker EE, Lombès A$, Prigione A$. Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders. Cell Stem Cell 2017; 20(5):659-674.e9

    Vavrova E, Lenoir V, Alves-Guerra MC, Denis RG, Castel J, Esnous C, Dyck JRB, Luquet S, Metzger D, Bouillaud F, Prip-Buus C. Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase 1 protects mice against high-fat/high-sucrose diet-induced insulin resistance. Am J Physiol Endocrinol Metab 2016; 311(3): E649-60

    Kremer LS, L’hermitte- Stead C, Lesimple P, Gilleron M, Filaut S, Jardel C, Haack TB, Strom TM, Meitinger T, Azzouz H, Tebib N, Ogier de Baulny H, Touati G, Prokisch H, Lombès A. Severe respiratory complex III defect prevents liver adaptation to prolonged fasting. J Hepatol 2016;65:377-385

    Hénique C, Mansouri A, Vavrova E, Lenoir V, Ferry A, Esnous C, Ramond E, Girard J, Bouillaud F, Prip-Buus C, Cohen I. Increasing mitochondrial muscle fatty acid oxidation induces skeletal muscle remodeling toward an oxidative phenotype. FASEB J. 2015 29(6):2473-83

    Esteves P, Pecqueur C, Ransy C, Esnous C, Lenoir V, Bouillaud F, Bulteau AL, Lombès A, Prip-Buus C, Ricquier D, and Alves-Guerra MC. Mitochondrial retrograde signaling mediated by UCP2 inhibits cancer cell proliferation and tumorigenesis. Cancer Research 2014 74(14):3971-821. Issue’s Cover.

    Helmy N, Prip-Buus C, Vons C, Lenoir V, Abou-Hamdan A, Guedouari-Bounihi H, Lombès A, Bouillaud F. Oxidation of hydrogen sulfide by human liver mitochondria. Nitric Oxide 2014; 41:105-12. 

     

     

    Team's news

     

    The team is actively participating to the French network GDR 3159 CNRS  “Réseau MeetOchondrie” that organizes an annual meeting (150-180 participants) as well as practical workshops on mitochondrial bioenergetics, physiology and pathology since 2007 (http://meetochondrie.ibgc.cnrs.fr/). CPB is Director since 2012, FB and AL are members of the executive committee.

    Team member of the DHU (Département Hospitalo-Universitaire) AUTHORS «Maladies hormonales et auto-immunes» created in 2013

    Daniel Ricquier, Vice-president of the French Academy of Science and elected Delegate for International Relations since January 2012

    Carina Prip-Buus, member of the "FOIE GRAS" european consortium (ETN-H2020, 2017-2020).

    Frédéric Bouillaud, French delegate for the European COST network on gaso-transmitters 2010-2015

    Anne Lombès Expert involved in the working groups on Common Data Elements for Mitochondrial Diseases within NIH/NINDS (National Institute of Health/ National Institute of Neurological Disorders and Stroke) in 2014-2015, see Mito Data Standards page.

    International Patent WO/2008/033990 - Compositions and methods for modulating the Notch signal transduction pathway. Inventors: Capobianco Anthony, Alves-Guerra MC