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    Mitochondrial fusion/fission machinery

    Mitochondrial fusion/fission machinery

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    ARNAUD CHEVROLLIER

    Arnaud chevrollier

    Lecturer

    arnaud.chevrollier @ univ-angers.fr

    Keywords : Mitochondria dynamics OPA1 ; mitophagy ; mitochondrial DNA  Nucleoids ; Super resolution imaging dSTORM

     

     

     

    State of the art and objectives              

    Mitochondria are organized in a dynamic connected network within cells, constantly adapting to cellular requirements by changing their shape and position through fission and fusion. Insights acquired over the past decade show that this dynamic plays a crucial role in many processes such as mitochondrial bioenergetics, axonal transport, calcium homeostasis, reactive oxygen species production and apoptosis. Mutations of genes coding for the fusion and fission proteins are responsible for mitochondrial network disorganization and fragmentation, leading to inherited diseases such as optic atrophy (OPA1 MIM# 16550)[5], or peripheral neuropathies (GDAP1 MIM#607831 ; MFN2 MIM#609260).

    Our research projects are centered on mitochondrial shaping, through genetic (http://mitodyn.org), biochemical and structural explorations of these organelles in patient samples and mouse models, and with a strong focus on mitochondrial dynamics impairments caused by mutations in OPA1[6],[7] MFN2[8, 9], GDAP1[10], DRP1[11] and OXPHOS genes

    The main objectives of our project 

    Determine the precise mechanisms of mitochondrial fusion/fission machinery to understand their pathogenesis and develop new therapies.

    We analyse by fluorescent microscopy the mitochondrial organization in case of fusion/fission defects. We reach nanoscale resolution by using STochastic Optical Reconstruction Microscopy, DSTORM.  A 3D multi-color super-resolution microscopy (SLSM, Single molecule localization microscopy ) to unravel the nanoscale spatial organization and interaction of the different mitochondrial targets.

    Scientific Partners 

    • Guy Lenaers 
    • Pascal Reynier
    • Vincent Proccacio
    • Valérie Desquiret Dumas
    • Naïg Gueguen
    • Cinzia Bocca
    • Salim Khiati
    • Majida Charif

     

    Main results from the last 5 years

    • Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. Kane SM, Chevrollier A.
    • The potential therapeutic effects of acetylation in severe dominant optic atrophy. Kane, A. Chevrollier
    • Nucleoid distribution and content in dominant optic atrophy Kane, A. Chevrollier.
    • Sporadic amyotrophic lateral sclerosis patients do not show ALS mitochondrial dynamic alterations. P Codron, A. Chevrollier. 
    • Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. S Gerber, M Charif, A. Chevrollier.

    People involved

    • Sophie Belal Scientific PhD in progress Since 2015 : Co-supervisor with Vincent Proccacio
    • Philippe Codron Scientific PhD in progress (Neurologist) Poste d’accueil INSERM Since 2016 : Co-supervisor Dr. J. Cassereau (Neurologist) : TDP-43 relocation and Mitochondrial stress in Amyotrophic Lateral Sclerosis. Collaboration J-P. Julien CERVO Brain Research Institute, Qc G1J 2G3, Canada Sept-2017-Juin 2018
    • Pascal Reynier; Cinzia Bocca
    • Charlène Lhuissier PhD student
    • Naïg Gueguen
    • Charlotte ORRE PhD student
    • Valérie Desquiret Dumas
    • Anaïs Girona Technician

     

    Main publications and patents from the 5 last years

    • Codron P, Chevrollier A, Kane SM, Echaniz-Laguna A, Latour P, Reynier P, Bonneau D, Verny C, Procaccio V, Lenaers G, Cassereau J. Increased mitochondrial fusion in a autosomal recessive CMT2A family with mitochondrial GTPase mitofusin 2 mutations. J Periph Nerv Syst. (2016 )Dec;21(4):365-369. doi: 10.1111/jns.12192.
    • Prunier F, Le Page S; Niro M, Fauconnier J, Cellier L, Tamareille S, Abdallah Gharib A, Chevrollier A, Loufrani, L, Grenier C, Kamel R, Sarzi E, Lacampagne A, Ovize M, Henrion D, Reynier P, Lenaers G, Mirebeau-Prunier D. Increase in cardiac ischemia-reperfusion injuries in Opa1+/- mouse model. PLOS one 2016 ; 11(10):e0164066.
    • Frey S, Geffroy G, Desquiret-Dumas V, Gueguen N, Bris C, Belal S, Amati-Bonneau P, Chevrollier A, Barth M, Henrion D, Lenaers G, Bonneau D, Reynier P, Procaccio V. The addition of ketone bodies alleviates mitochondrial dysfunction by restoring complex I assembly in a MELAS cellular model. Biochim Biophys Acta. 2016 ;1863(1):284-291. DOI: 10.1016/j.bbadis.2016.10.028
    • Kane SM, Alban J, Desquiret-Dumas V, Gueguen N, Ishac L, Ferre M, Amati-Bonneau P, Procaccio V, Bonneau D, Lenaers G, Reynier P, Chevrollier A. Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. JCMM, (2017) 21(10):2284-2297. DOI: 10.1111/jcmm.13149
    • Wakim J, Goudenege D, Perrot R, Gueguen N, Desquiret-Dumas V, de la Barca JMC, Rosa ID, Manero F, Le Mao M, Chupin S, Chevrollier A, Procaccio V, Bonneau D, Logan DC, Reynier P, Lenaers G, Khiati S. CLUH couples mitochondrial distribution to the energetic and metabolic status. J Cell Sci. (2017) 130(11):1940-1951. doi: 10.1242/jcs.201616
    • Gerber S1, Charif M1, Chevrollier A2, Chaumette T2, Angebault C, Kane MS, Paris A, Alban J, Quiles  M, Delettre C, Bonneau D, Procaccio V, Amati-Bonneau P, Reynier P, Leruez S, Calmon R, Boddaert N, Funalot B, Rio M, Bouccara D, Meunier I, Sesaki  H, Kaplan J, Hamel CP, Rozet JM, Lenaers G. Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission. Brain () (1, 2 equal contribution) PMID: 28969390 DOI: 10.1093/brain/awx219
    • Zein S, Francisa Z, Montarou G, Chandez F, Kane MS, Chevrollier A.  Microdosimetry of 250 keV photons in a 3D realistic mitochondria phantom using Geant4 Monte Carlo code. (2017) Physica Medica, 42:7-12. doi: 10.1016/j.ejmp.2017.08.005.
    • Geffroy G, Benyahia R, Frey S, Desquiret-Dumas V, Gueguen N, Bris C, Belal S, Inisan A, Renaud A, Chevrollier A, Henrion D, Bonneau D, Letournel F, Lenaers G, Reynier P, Procaccio V. The accumulation of assembly intermediates of the mitochondrial complex I matrix arm is reduced by limiting glucose uptake in a neuronal-like model of MELAS syndrome. Biochim Biophys Acta. 2018 ;1864(5 Pt A):1596-1608. doi: 10.1016/j.bbadis.2018.02.005
    • Bocca C, Kouassi Nzoughet J, Leruez S, Amati-Bonneau P, Ferré M, Kane MS, Veyrat-Durebex C, Chao de la Barca JM, Chevrollier A, Homedan C, Verny C, Miléa D, Procaccio V, Simard G, Bonneau D, Lenaers G, Reynier P. A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders. Invest Ophthalmol Vis Sci. 2018 ;59(1):185-195. doi: 10.1167/iovs.17-23027.
    • Codron P, Cassereau J, Vourc'h P, Veyrat-Durebex C, Blasco H, Kane  MS, Procaccio V, Letournel F, Verny C, Lenaers G, Reynier P, Chevrollier A.  Primary fibroblasts derived from sporadic amyotrophic lateral sclerosis patients do not show ALS histopathological lesions Amyotroph Lateral Scler Frontotemporal Degener. 2018 ;19(5-6):446-456. doi: 10.1080/21678421.2018.1431787.
    • Bocca C, Kane MS, Veyrat-Durebex C, Chupin S, Alban J, Kouassi Nzoughet J, Le Mao M, Chao de la Barca JM, Amati-Bonneau P, Bonneau D, Procaccio V, Lenaers G, Simard G, Chevrollier A, Reynier P. The Metabolomic Bioenergetic Signature of Opa1-Disrupted Mouse Embryonic Fibroblasts Highlights Aspartate Deficiency. Sci Rep. 2018 Aug 1;8(1):11528. doi: 10.1038/s41598-018-29972-9.

    Collaborations

    • Hiromi Sesaki, Ph.D. Professor Department of Cell Biology Johns Hopkins University School of Medicine Hunterian 119, 725 N. Wolfe Street, Baltimore, MD 21205
    • Patrick Yu-Wai-Man Wellcome Trust Centre for Mitochondrial Research Institute of Genetic Medicine Newxastle University
    • Jean-Baptiste Sibarita ;  Rémi Galland ; Imagerie Cellulaire Quantitative Universite de Bordeaux IINS - UMR 5297 - Bat. Centre Broca Nouvelle-Aquitaine