Job offer: postdoctoral Fellow Project Title: Mitoheart-Mitochondrial genome instability and cardiac aging Research Fields: Mitochondria; Genome instability; Aging; Cardiovacular diseases Work Place: Angers, France Research Laboratory(ies) Laboratory(ies): (ies): UMR CNRS 6015 – INSERM 1083, Mitovasc, Team Mitolab UBL Research Department: Department: Biology and Health Head(s) Head(s) of the Scientific Project: roject: Olivier BARIS / Guy Lenaers Offer type: postdoctoral researcher (sho short term contract, contract, 12 months, months, possibly once renewable)) Hiring Institution: University of Angers Application deadline: deadline: 30/11/2017 Job Starting Date: Date: 01/02/2018

Environment The University of Angers is a highly dynamic Institution including 6 formation departments, one being specific of «the biology of health ». This department includes among others, two research units involved in cardio-vascular, mitochondrial and metabolic research concerning common and inherited diseases (http://www.univangers.fr/en/research/research-policy.html). This department is supported by a transversal “ICAT federative research structure” providing technical platforms (http://www.icat4208.univ-angers.fr/fr/index.html) and fostering the internal and external scientific communication. The MitoVasc Unit (http://mitovasc.univ-angers.fr/en/index.html), labelized by the CNRS (UMR 6015) and the INSERM (U1083) on the 01/01/2017, is at the heart of the research investigations of the MitoVasc Institute that includes all the translational studies with the University Hospital services (http://www.univangers.fr/fr/recherche/actualites/mitovasc-2.html) . The MitoVasc Unit includes two teams, one led by Dr. Daniel Henrion focusing on cardiovascular investigations, with the contribution of Pr. Fabrice Prunier, and one led by Guy Lenaers, dedicated to investigations on inherited mitochondrial diseases. Both teams are fully equipped with high standard technologies to perform in vitro (cell biology, histology, high resolution fluorescent microscopy, NGS, mass spectrometry, mitochondrial physiology assessment) and in vivo (mouse cardiac and vascular physiology) experiments. Their researches are fostered to promote clinical transfers back to the cohorts of patients that are recruited in the University Hospital. The project proposed here is located at the interface between the two Mitovasc teams, starting by the manipulation and assessment of mitochondrial physiology, and ending by the evaluation of cardiac functions in mice, with further the expectation to develop novel therapeutic routes to be tested locally on patients.

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Mission (scientific project) Despite active scientific research and improved prevention, cardiovascular diseases are still a major issue in public health, especially in our aging society, and a leading cause of death. In particular, the incidence of cardiac arrhythmias, which are life-threatening conditions, is drastically increasing with age, but the mechanisms involved are not fully understood. We have recently shown that the accumulation of mitochondrial DNA deletions in cardiomyocytes, and the ensuing mosaic pattern of mitochondrial deficiency in the heart are promoting ventricular arrhythmia (Baris et al., 2015), thus establishing a plausible link between aging and this pathological heart condition. Interestingly, mitochondrial dynamics and mitophagy are important for the clearance of mutated mtDNA molecules, suggesting that interfering with those cellular processes in cardiomyocytes during aging might be either beneficial or eventually detrimental. Therefore, using mouse models with accelerated accumulation of mtDNA deletions in the myocardium (K320E-TwinkleMyo), and altered mitochondrial fusion (Opa1+/-) or fission (DRP+/-) capacity, we will evaluate how mitochondrial dynamics impinge with the development of age-related cardiac arrhythmias. Moreover, we will determine whether therapeutic approaches involving drugs known to alter mitochondrial fusion/fission and mitophagie capacities can be used to prevent the development of cardiac rhythm disorders.

Required Profile Doctor (PhD) in Biology, maximum 3 years of experience after thesis defense1. An international experience in research is required (during or after Doctorate). Candidates must not have supported their thesis in the hiring institution and not previously worked in the host research unit. The candidate must be highly competent in mouse experiments, as the project includes the maintenance of various mouse lines and complex breeding strategies. A solid background in cell and molecular biology is also required. Knowledges in mitochondrial and/or cardiac physiology are welcome.

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The thesis defense must have taken place after 31/08/2014, except in rare exceptions. Periods of sickness, maternity or parental leave shall not be counted in this 3 years period.

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Usefull References - Andreux PA, Houtkooper RH, Auwerx J. (2013) Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov. 12(6):465-83. - Baris OR, Ederer S, Neuhaus JF, von Kleist-Retzow JC, Wunderlich CM, Pal M, Wunderlich FT, Peeva V, Zsurka G, Kunz WS, Hickethier T, Bunck AC, Stöckigt F, Schrickel JW, Wiesner RJ. (2015). Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell Metabolism 21(5), 667-677. - Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, Chan DC. (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 141(2):280-9. - Dai Y, Zheng K, Clark J, Swerdlow RH, Pulst SM, Sutton JP, Shinobu LA, Simon DK. (2014) Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation. Hum Mol Genet. 23(3):637-47. - Khrapko K, Bodyak N, Thilly WG, van Orsouw NJ, Zhang X, Coller HA, Perls TT, Upton M, Vijg J, Wei JY. (1999) Cellby-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions. Nucleic Acids Res. 27(11):2434-41. - Kurihara Y, Kanki T, Aoki Y, Hirota Y, Saigusa T, Uchiumi T, Kang D. (2012) Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast. J Biol Chem. 287(5):3265-72. - Le Page S, Niro M, Fauconnier J, Cellier L, Tamareille S, 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, Prunier F. (2016) Increase in Cardiac Ischemia-Reperfusion Injuries in Opa1+/- Mouse Model. PLoS One. 11(10):e0164066. - Muthuramu I, Lox M, Jacobs F, De Geest B. (2014) Permanent ligation of the left anterior descending coronary artery in mice: a model of post-myocardial infarction remodelling and heart failure. J Vis Exp (94).

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How to apply ? Please send the following documents by email to: Olivier Baris ([email protected]); Guy Lenaers ([email protected]) and the research department of UBL ([email protected]): Short Curriculum Vitae and a covering letter showing your interest and especially addressing your professionnel project A list of your major works (2 pages max.) : scientific publications, patents and others scientific productions Letters of recommendation (not required) A copy of your PhD diploma2 The general selection process is described here : https://u-bretagneloire.fr/dossiers/postdoc/candidatures Selection Jury : Olivier Baris ; Daniel Henrion ; Guy Lenaers Audition dates: December 2017-January 2018

Further information Annual Gross Salary : To be determined This Fellowship is cofunded by Université Bretagne Loire and UMR CNRS 6015 – INSERM 1083, Mitovasc The Université Bretagne Loire federates 7 universities, 15 “grandes écoles” and 5 research organiations in the West of France (Bretagne and Pays de la Loire). This community of universities and institutions aims to develop the scientific and academic potential of this territory at national and international level. The MitoVasc Unit (http://mitovasc.univ-angers.fr/en/index.html), labelized by the CNRS (UMR 6015) and the INSERM (U1083) on the 01/01/2017, is at the heart of the research investigations of the MitoVasc Institute that includes all the translational studies with the University Hospital services (http://www.univangers.fr/fr/recherche/actualites/mitovasc-2.html) .

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For doctors graduated from a French establishment, a link to the thesis notice in the SUDOC Catalogue or the French official portal Theses.fr is sufficient.

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