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Publications à l'affiche Conférences

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Kagan VE, Jiang J, Huang Z, Tyurina YY, Desbourdes C, Cottet-Rousselle C, Dar HH, Verma M, Tyurin VA, Kapralov AA, Cheikhi A, Mao G, Stolz D, St Croix CM, Watkins S, Shen Z, Li Y, Greenberg ML, Tokarska-Schlattner M, Boissan M, Lacombe ML, Epand RM, Chu CT, Mallampalli RK, Bayır H, Schlattner U. Cell Death Differ. 2016 Jan 8. doi: 10.1038/cdd.2015.160. [Epub ahead of print]

A 9-wk docosahexaenoic acid-enriched supplementation improves endurance exercise capacity and skeletal muscle mitochondrial function in adult rats. Le Guen M, Chaté V, Hininger-Favier I, Laillet B, Morio B, Pieroni G, Schlattner U, Pison C, Dubouchaud H. Am J Physiol Endocrinol Metab. 2016 Feb 1;310(3):E213-24.

Modelling in vivo creatine/phosphocreatine in vitro reveal divergent adaptations in human muscle mitochondrial respiratory control by ADP after acute and chronic exercise. Ydfors M, Hughes MC, Laham R, Schlattner U, Norrbom J, Perry CG. J Physiol. 2015 Dec 3. doi: 10.1113/JP271259. [Epub ahead of print]

Characterization and production of protein complexes by co-expression in Escherichia coli. Haffke M, Marek M, Pelosse M, Diebold ML, Schlattner U, Berger I, Romier C. Methods Mol Biol. 2015;1261:63-89. doi: 10.1007/978-1-4939-2230-7_4.

Erythropoietin and its derivates modulate mitochondrial dysfunction after diffuse traumatic brain injury. Millet A, Bouzat P, Trouve Buisson T, Batandier C, Pernet Gallay K, Gaide Chevronnay L, Barbier E, Debillon T, Fontaine E, Payen JF. J Neurotrauma. 2015 Nov 4. [Epub ahead of print]

Liver mitochondrial function in ZDF rats during the early stages of diabetes disease. Vial G, Le Guen M, Lamarche F, Detaille D, Cottet-Rousselle C, Demaison L, Hininger-Favier I, Theurey P, Crouzier D, Debouzy JC, Dubouchaud H, Fontaine É. Physiol Rep. 2016 Feb;4(3). pii: e12686. doi: 10.14814/phy2.12686. Epub 2016 Feb 4.

Gut microbiota richness promotes its stability upon increased dietary fibre intake in healthy adults. Tap J, Furet JP, Bensaada M, Philippe C, Roth H, Rabot S, Lakhdari O, Lombard V, Henrissat B, Corthier G, Fontaine E, Doré J, Leclerc M. Environ Microbiol. 2015 Dec;17(12):4954-64

Respective effects of oxygen and energy substrate deprivation on beta cell viability. Lablanche S, Cottet-Rousselle C, Argaud L, Laporte C, Lamarche F, Richard MJ, Berney T, Benhamou PY, Fontaine E. Biochim Biophys Acta. 2015 Jun-Jul;1847(6-7):629-39

Five-Year Metabolic, Functional, and Safety Results of Patients With Type 1 Diabetes Transplanted With Allogenic Islets Within the Swiss-French GRAGIL Network. Lablanche S, Borot S, Wojtusciszyn A, Bayle F, Tétaz R, Badet L, Thivolet C, Morelon E, Frimat L, Penfornis A, Kessler L, Brault C, Colin C, Tauveron I, Bosco D, Berney T, Benhamou PY; GRAGIL Network. Diabetes Care. 2015 Sep;38(9):1714-22

Malignant insulinoma may arise during the course of type 1 diabetes mellitus: A case report. Lablanche S, Chobert-Bakouline M, Risse O, Laverrière MH, Chabre O, Benhamou PY. Diabetes Metab. 2015 Jun;41(3):258-61

Regulation of the proteome by amino acids. Bourgoin-Voillard S, Goron A, Seve M, Moinard CProteomics. 2016 Jan 19. doi: 10.1002/pmic.201500347. [Epub ahead of print] Review.

Arginine behaviour after arginine or citrulline administration in older subjects. Moinard C, Maccario J, Walrand S, Lasserre V, Marc J, Boirie Y, Cynober L. Br J Nutr. 2016 Feb;115(3):399-404. doi: 10.1017/S0007114515004638. Epub 2015 Dec 1.

Combining citrulline with atorvastatin preserves glucose homeostasis in a murine model of diet-induced obesity. Capel F, Chabrier G, Pitois E, Rigaudière JP, Le Plenier S, Durand C, Jouve C, de Bandt JP, Cynober L, Moinard C, Morio B. Br J Pharmacol. 2015 Oct;172(20):4996-5008

Citrulline Supplementation Induces Changes in Body Composition and Limits Age-Related Metabolic Changes in Healthy Male Rats. Moinard C, Le Plenier S, Noirez P, Morio B, Bonnefont-Rousselot D, Kharchi C, Ferry A, Neveux N, Cynober L, Raynaud-Simon A.J Nutr. 2015 Jul;145(7):1429-37

Citrulline and nitrogen homeostasis: an overview. Breuillard C, Cynober L, Moinard C. Amino Acids. 2015 Apr;47(4):685-91. doi: 10.1007/s00726-015-1932-2

Whole Rye Consumption Improves Blood and Liver n-3 Fatty Acid Profile and Gut Microbiota Composition in Rats.  Ounnas F, Privé F, Salen P, Gaci N, Tottey W, Calani L, Bresciani L, López-Gutiérrez N, Hazane-Puch F, Laporte F, Brugère JF, Del Rio D, Demeilliers C, de Lorgeril M. PLoS One. 2016 Feb 10;11(2):e0148118. doi: 10.1371/journal.pone.0148118. eCollection 2016.

Chronic exposure to low-level cadmium in diabetes: role of oxidative stress and comparison with polychlorinated biphenyls. Jacquet A, Ounnas F, Lenon M, Arnaud J, Demeilliers C, Moulis JM. Curr Drug Targets. 2015 May 31. [Epub ahead of print]

Wheat aleurone fractions and plasma n-3 fatty acids in rats. Ounnas F, Salen P, Demeilliers C, Calani L, Scazzina F, Hazane-Puch F, Laporte F, Melegari C, Del Rio D, de Lorgeril M.Int J Food Sci Nutr. 2015;66(4):391-4

RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up. Franko B, Benhamou PY, Genty C, Jouve T, Nasse L, Rzeoecki V, Semeraro P, Stasia MJ, Zaoui P. Acta Diabetol. 2015 Nov 25. [Epub ahead of print]

Fractionation and proteomic analysis of the Walterinnesia aegyptia snake venom using OFFGEL and MALDI-TOF-MS techniques. Abd El Aziz TM, Bourgoin-Voillard S, Combemale S, Beroud R, Fadl M, Seve M, De Waard M. Electrophoresis. 2015 Oct;36(20):2594-605

A low-cost system to easily measure spontaneous physical activity in rodents. Chabert C, Bottelin P, Pison C, Dubouchaud H. J Appl Physiol (1985). 2016 Feb 18:jap.00888.2015. doi: 10.1152/japplphysiol.00888.2015. [Epub ahead of print]

Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial. Deslée G, Mal H, Dutau H, Bourdin A, Vergnon JM, Pison C, Kessler R, Jounieaux V, Thiberville L, Leroy S, Marceau A, Laroumagne S, Mallet JP, Dukic S, Barbe C, Bulsei J, Jolly D, Durand-Zaleski I, Marquette CH; REVOLENS Study Group. JAMA. 2016 Jan 12;315(2):175-84. doi: 10.1001/jama.2015.17821.

Ex vivo lung graft perfusion. Briot R, Gennai S, Maignan M, Souilamas R, Pison C. Anaesth Crit Care Pain Med. 2015 Dec 30. [Epub ahead of print]

Cinnamon intake alleviates the combined effects of dietary-induced insulin resistance and acute stress on brain mitochondria. Couturier K, Hininger I, Poulet L, Anderson RA, Roussel AM, Canini F, Batandier C. J Nutr Biochem. 2016 Feb;28:183-90. Epub 2015 Nov 10.

 

 

Salle de réunion - 2è étage




Stages et thèses

 

Sujets de thèse LBFA pour candidater à l'EDCSV jusqu'au 13 avril

Post-translational modifications of mitochondrial therapeutic targets
Modifications post-traductionnelles de cibles thérapeutique mitochondriales
Context - Mitochondria are organelles involved in energy homeostasis and cell death. Several drugs, already in used in medicine or under development, act on mitochondrial proteins by a poorly understood mechanism.
Objective - On the basis of our previous studies, the objective of this project is to test whether metformin (an indirect inhibitor of Complex I of the respiratory chain) and the opening of the permeability transition pore (a mitochondrial channel involved in cell death) induced post-translational modifications of mitochondrial proteins.
Methods - Three approaches will be used.
(1) Detection of secondary protein modifications induced by Metformin or under conditions of PTP opening. We intend to analyze mitochondrial proteins from (i) liver mitochondria isolated from control rats and rats treated by Metformin, a condition previously reported to induce Complex I inhibition, and (ii) isolated rat liver mitochondria before and after PTP opening induced by Ca2+-overload. Proteins will be separated under denaturing conditions in large gel 1D-PAGE and stained or immunoblotted for various secondary modifications (oxidation, phosphorylation, acetylation, glutathionylation, nitrosylation, methylation, ubiquitinylation). This approach should give first indications on the nature and frequency of secondary modifications that correlate with Complex I inhibition or PTP opening.
(2) Identification of changes in the mitochondrial proteome induced by Metformin or under conditions of PTP opening. To go a step further, we will separate mitochondrial proteins obtained from the same experimental models as above by using gel-based 2D-techniques, either DIGE or classical 2D-PAGE, followed by staining or immunodetection of secondary modifications. Although these techniques will not resolve all mitochondrial membrane proteins, they will allow confirming some of the observed secondary modifications, possibly detect further modifications (e.g. proteolysis) or changes in protein abundance, and most importantly allow an analysis of the suspicious protein spots by mass spectrometry. This will reveal the identity of the concerned protein(s) as well as the putative secondary modifications.
(3) Conformational changes in Complex I induced by Metformin or under conditions of PTP opening. The rationale of this approach is that secondary modifications of Complex I, if occurring, should induce some conformational changes to alter its function. Most of these secondary modifications, and thus the altered conformation, should be preserved upon isolation of native complex. We will thus purify Complex I from solubilized rat liver mitochondria by ultracentrifugation according to established protocols. Alternatively, we will try to establish a rapid isolation procedure based on immune-affinity techniques. Subunits of Complex I will be then analyzed by 1D-PAGE separation and immunoblotting for secondary modifications. Importantly, native Complex I will also be subjected to limited proteolysis by different proteases as a measure for conformational changes. Affected subunits revealed by 1D-PAGE will be identified by mass spectrometry. This approach is independent of the former ones and can be realized even if these yield too few or too many candidate proteins.

Expected results - Considering that metformin is widely used, while there is good probability that the permeability transition pore will soon become a therapeutic target in numerous diseases related to ischemia-perfusion injury, the comprehensive description of the post-translational modification of the mitochondrial proteins would indisputably represent a major progress in mitochondrial physiology applied to clinical medicine.

Contact: Pr Eric Fontaine
e-mail: eric.fontaine@ujf-grenoble.fr
tel. 04 76 63 56 01
Lien EDCSV:http://doctorat.univ-grenoble-alpes.fr/fr/preparer-un-doctorat/les-sujets-de-these/choisir-son-sujet-de-these-575208.htm?RH=GUCEDFR_PREECD


Signalisation dans la cardiotoxicité des anthracyclines : perspectives pour diagnose et  traitement
Cell signaling in anthracycline cardiotoxicity: perspectives for diagnosis and treatment
Context – Anthracyclines, in particular doxorubicin, are the most effective and commonly used anticancer drugs. However, their clinical use is limited by a risk of cardiotoxicity. The cardiotoxic side effects represent a major problem of anthracycline chemotherapy and a burden to the public health system. Despite 40 years of research, understanding of anthracyclines’ cardiotoxicity remains a challenge in terms of involved mechanisms and prevention.
Objective –  On the basis of our previous studies, we put forward a novel hypothesis, namely that anthracycline-induced cardiac damage is related to an impaired cellular signaling response to energy depletion. This can lead to a “catastrophe”, fatal for cardiac (and in fact also cancer) cells. The project will validate and extend this hypothesis by addressing further mechanistic aspects, as cell type specific differences, but mainly explore translational aspects by designing and testing cardiac protective strategies in an animal model.
Methods – The integrative project will
(i) apply novel tools to follow and dissect cell signaling in cellular (cardiomyocytes) and mouse models  of doxorubicin toxicity. This includes the in cellulo application of a newly developed intracellular fluorescent “energy sensor”, and the set-up and characterization of a transgenic mouse model (inducible, cardiac-specific) showing impaired cell signaling.
(ii) screen inhibitory effects on cell signaling beyond adult cardiomyocytes, using other cardiac and non-cardiac cells (including cancer cells), different developmental states of cardiac cells, transplant patient’s heart samples, and in particular to look at cells accessible in blood (leukocytes) of mice and human patients for possible diagnostic purposes.
(iii) use a preclinical approach to systematically screen kinase-activating treatments, alone or in combination, for their protective effects on DXR cardiotoxicity, using isolated cardiomyocytes and the mouse model for chronic  anthracycline toxicity.
This work involves isolation of primary cells (cardiomyocytes and others), confocal microscopy (immunocyto/histochemistry), biochemical analysis (immunodetection, immunoprecipitation, enzyme assays), as well as work with transgenic mice (deletion of transgene, doxorubicin treatment, echocardiography, exercise assays).
Expected results – Knowledge resulting from this project is likely to provide means to modulate cardiotoxic and anticancer action of the drug. This may include the design of modified application regimes, the use of cardioprotectants, or the identification of diagnostic markers. Moreover new insight into the development of impaired cellular stress response could go beyond doxorubicin cardiotoxicity and help to understand other forms of cardiac injury.

Contact: Dr Malgorzata Tokarska-Schlattner
malgorzata.tokarska-schlattner@ujf-grenoble.fr
04 76 63 53 99 or 476 51 46 70
Lien EDCSV: http://doctorat.univ-grenoble-alpes.fr/fr/preparer-un-doctorat/les-sujets-de-these/choisir-son-sujet-de-these-575208.htm?RH=GUCEDFR_PREECD