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Mitochondria, Neurosteroids and Biological Rhythms: Implications in Health and Disease States

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Mitochondria, Neurosteroids and Biological Rhythms: Implications in Health and Disease States Mitochondria, neurosteroids and biological rhythms : implications in health and disease states Amandine Grimm To cite this version: Amandine Grimm. Mitochondria, neurosteroids and biological rhythms : implications in health and disease states. Neurobiology. Université de Strasbourg, 2015. English. NNT : 2015STRAJ002. tel-01280544 HAL Id: tel-01280544 https://tel.archives-ouvertes.fr/tel-01280544 Submitted on 29 Feb 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSIT DE STRASBOURG Ecole Doctorale des Sciences de la Vie et de la Sant (ED 414) INSERM UMR_S U1119 M Biopathologies de la My line, Neuroprotection et Strat gies Th rapeutiques THSE En cotutelle avec lRUniversit de Ble, Suisse pr sent e par : Amandine GRIMM soutenue le 14 janvier 2015 pour obtenir le grade de : Docteur de lRUniversit de Strasbourg Sp cialit : Neurosciences Mitochondria, neurosteroids and biological rhythms: implications in health and disease states. THSE dirig e par : M. MENSAH-NYAGAN Ayiko , Guy Professeur, Universit de Strasbourg, France Mme ECKERT Anne Professeur, Universit de Ble, Suisse RAPPORTEURS : M. HAMBURGER Matthias Professeur, Universit de Ble, Suisse M. REICHERT Heinrich Professeur, Universit de Ble, Suisse AUTRES MEMBRES DU JURY : Mme MATHIS Chantal Docteur, Universit de Strasbourg, France Mme PATTE-MENSAH Christine Docteur, Universit de Strasbourg, France À +#1 .0#,21 À +#1 $0L0#1 #2 130 À 2-31 !#36 /3# (_'+# #2 /3' +_-,2 1-32#,3 2-32 3 *-,% "3 !&#+', ACKNOWLEDGMENTS The present thesis has been performed between the Neurobiology Laboratory for Brain Aging and Mental Health of the Psychiatric University Clinics of Basel (UPK), University of Basel, under the supervision of Prof. Dr. Anne Eckert, and the INSERM unit U1119, Biopathologie de la My line, Neuroprotection et Strat gies Th rapeutiques, Universit de Strasbourg, under the supervision of Prof. Dr. Ayikoe Guy Mensah-Nyagan. My warmest thanks go to Prof. Dr. Anne Eckert who allowed me to be part of her team for this joint-PhD thesis. Thanks for your trust, your support and all the scientific opportunities you gave me (congresses, publications...). You have allowed me to develop my scientific skills by giving me new technical and intellectual challenges that helped me to grow up both professionally and personally. I would like to express my gratitude to Prof. Dr. Ayikoe Guy Mensah-Nyagan who always believed in my scientific skills since the Master degree. First, you gave me the opportunity to perform my Master training in Montreal which was one of the best experiences in my life. Then, you advised me as a PhD student to Prof. Dr. Anne Eckert and allowed me to do this joint-PhD thesis with your lab. I am indebted for your teaching, your availability, your advices and your constant support. My thanks go to Prof. Dr. Matthias Hamburger who accepted to be my Faculty representative and to Dr. Chantal Mathis for making herself available as a co-referee. I also wish to acknowledge Prof. Dr. Heinrich Reichert and Dr. Christine Patte-Mensah for their participation in my dissertation. I would like to express my thanks and my sympathy for my colleagues in Basel: First, a big thank goes for Karen, my colleague and shill, for all the time we spent together in the lab (even during night work), in congresses and in private. Thanks for all the outstanding scientific (and less scientific) conversations. Thanks a lot Fides for your help (especially the administrative part) and your humor that was always a breath of fresh air in critical periods. Thanks to Ginette and Imane for these moments of conviviality during the coffee break. We shared joy, tears, blues but, above all, happiness. Thanks for all these moments that make me think of you all a little bit like a second family. I would like also to thank all the "zivis" who stopped by our lab for a few months, in particular Stefano, Fabio, Ricky and Jonas, for their help in the lab or with informatic tasks that made my life much easier at the end! Thanks also to Virginie and Julien for all the "afterwork meetings" where we shared interesting (and funny) scientific (or not) conversations. Toute ma sympathie va galement mes coll gues de Strasbourg: Dr. V ronique Kemmel pour tous les changes scientifiques que l'on a pu avoir, Dr. Christine Patte-Mensah pour ses conseils et son ind fectible bonne humeur, Dr. Laurence Meyer, Dr. Christian Klein, David Hollinger, et bien sr tous les autres (Professeurs, docteurs, postdocs, techniciens et tudiants...) pour l'aide et les conseils qu'ils ont pu m'apporter. ACKNOWLEDGMENTS Un grand merci au Dr. Guillaume Wendt, mon binme depuis le Master, pour son soutien moral dans les moments difficiles et sa bonne humeur communicative! La route n'a pas t facile mais on y est finalement arriv ! Du fond du cLur , je voudrais remercier mes amis et ma famille: Merci Diane, lose et Sandrine pour tous ces bons moments pass s ensemble depuis le coll ge et le lyc e. Merci pour votre coute et votre soutien qui ont contribu faire de moi celle que je suis aujourd'hui. Merci ma cousine, Eve et ses adorables enfants, ainsi qu' mon groupe de danse du jeudi soir pour ces moments d' vasion et de convivialit loin du labo. Votre soutien et votre bonne humeur ont t pour moi une incroyable bouff e d'air frais! Merci mes grands-m res et grands-p res, ma marraine et mon parrain (partis trop tt), et tous les autres pour leur foi en moi qui m'a port aussi loin. Un immense merci toi, Benjamin, pour toutes ces ann es pass es mes ct s. Merci pour ton ind fectible soutient dans les moments de doute, merci pour ton humour qui me remonte toujours le moral, merci ta patience quand moi j'en manquais, et merci d'tre l pour en voir le fruit! Je tiens galement chaleureusement remercier Mado, Joseph et C cilia pour leur coute, leur soutien et leur gentillesse. Merci vous! Et enfin, comme il est coutume de garder le meilleur pour la fin, je ne remercierai jamais assez mes parents pour avoir toujours cru en moi et m'avoir soutenu depuis le tout d but. Vous m'avez donn l'envie et la motivation de vouloir aller toujours plus haut, toujours plus loin, et vous m'avez transmis la force et les qualit s n cessaires pour y arriver. Merci galement mes fr res et sLur , en particulier Maxime, qui a t un super stagiaire pendant quelques semaines et qui m'a toujours soutenu, et Laura, toujours prte rendre service (merci petite sLur !). La route a t longue mais votre amour et votre confiance m'ont permis de me construire petit petit. Aujourd'hui je suis tr s fi re et tr s heureuse de partager cet aboutissement avec vous. Ainsi, je d die cette th se ceux que j'aime et qui m'ont port jusqu'ici. TABLE OF CONTENT TABLE OF ILLUSTRATIONS: INTRODUCTION AND CONCLUSION ................................. 3 LIST OF APPENDICES ........................................................................................................ 4 SUMMARY ............................................................................................................................ 5 I. INTRODUCTION ........................................................................................................ 9 A. Mitochondria...........................................................................................................10 1. Mitochondrial structure and pivotal roles within cells ...........................................10 a) Mitochondria: versatile organelles ...................................................................11 (i) Mitochondrial fission ....................................................................................13 (ii) Mitochondrial fusion .....................................................................................13 (iii) Mitophagy ....................................................................................................15 b) Orchestrating cellular energy production .........................................................15 (i) Cellular glycolysis ........................................................................................16 (i) Mitochondrial respiration ..............................................................................17 (ii) Bioenergetic state and mitochondrial shape.................................................19 c) Mitochondrial: paradoxical organelles .............................................................20 (i) Mitochondria: source and target of reactive oxygen and nitrogen species ...20 (ii) Antioxidant defenses: weapons against oxidative stress ..............................22 (iii) Mitochondria and cell suicide .......................................................................23 2. Mitochondrial dysfunction in AlzheimerRs disease ...............................................25 a) Clinical symptoms and etiological factors ........................................................26 b) Histopathological hallmarks .............................................................................28 (i) Neurofibrillary tangles and hyperphosphorylated tau ...................................28 (ii) Amyloidogenic
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