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Research > Team Mitochondria, Stress and Cell Death

Mitochondria, Stress and Cell Death

Principal Investigator : Stephen Manon

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Team Members

Claude Bobo - AI CNRS

Nadine Camougrand - DR2 CNRS

Cecile Gonzalez - MCU UB

Stephen Manon - DR2 CNRS

Muriel Priault - CR1 CNRS

Pierre Vigié - Doctorant MESR

 

Summary

Our team is interested in several aspects of the role of mitochondria as a target and a mediator of autophagy and apoptosis, two processes that are crucial for cellular homeostasis, and of which alterations are involved in a number of pathologies, such as cancer, neurodegenerative diseases and ageing-related diseases. Our projects involve studies on yeast, mammalian cells and reconstituted systems.

 

Research activity

1 - Molecular mechanisms underlying the interaction of the pro-apoptotic protein Bax with mitochondria (Stéphen Manon). This research axis uses simplified models, namely the heterologous expression in yeast, to investigate different aspects of the regulation of the dynamic interaction between Bax and mitochondria during apoptosis, namely its phosphorylation and its interaction with the anti-apoptotic protein Bcl-xL. A sub-axis involving structural studies of Bax, is animated by an assistant-professor (Cécile Gonzalez).

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2 - Pro-survival function of Bcl-xL(Muriel Priault). When overexpressed, Bcl-xL is responsible for the survival of tumor cells, not only because of its well-documented inhibitory effect of Bax function, but also because of its ability to stimulate autophagy and food intake. These functions of Bcl-xL are regulated by post-translational modifications, such as the deamidation of two Asn residues, and the interaction of Bcl-xL with the small GTPase Rab7, through a domain distinct from the BH3-binding site involved in the interaction with other Bcl-2 family members such as Bax.

 

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3 - Function and regulation of mitophagy (Nadine Camougrand). The selective elimination of mitochondria is a major process in the cellular adaptation to stress conditions and mitochondria alterations. This process has been first characterized in the lab, in yeast cells grown under strict respiratory conditions. We have shown that, depending on the initial trigger, different signalling pathways are leading to mitophagy and/or to general autophagy. Our project aims at characterizing the molecular events underlying these pathways.

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Key and active collaborations (internal and external)

 

Fundings 2009-14

 

Keywords

Apoptosis - Autophagy - Mitochondria – Cancer - Ageing

 

Selected publications 2009-2017

Vigié P, Camougrand N. [Role of mitophagy in the mitochondrial quality control]. Med Sci (Paris). 2017 Mar;33(3):231-237

Garenne D, Renault TT, Manon S. Bax mitochondrial relocation is linked to its phosphorylation and its interaction with Bcl-xL. Microb Cell. 2016 Dec 5;3(12):597-605

Trindade D, Pereira C, Chaves SR, Manon S, Côrte-Real M, Sousa MJ. VDAC regulates AAC-mediated apoptosis and cytochrome <i>c</i> release in yeast. Microb Cell. 2016 Aug 25;3(10):500-510

Simonyan L, Légiot A, Lascu I, Durand G, Giraud MF, Gonzalez C, Manon S. The substitution of Proline 168 favors Bax oligomerization and stimulates its interaction with LUVs and mitochondria. Biochim Biophys Acta. 2017 Jun;1859(6):1144-1155

Villar VH, Nguyen TL, Delcroix V, Terés S, Bouchecareilh M, Salin B, Bodineau C, Vacher P, Priault M, Soubeyran P, Durán RV. mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation. Nat Commun. 2017 Jan 23;8:14124

Régnacq M, Voisin P, Sere YY, Wan B, Soeroso VM, Bernard M, Camougrand N, Bernard FX, Barrault C, Bergès T. Increased fatty acid synthesis inhibits nitrogen starvation-induced autophagy in lipid droplet-deficient yeast. Biochem Biophys Res Commun. 2016 Aug 12;477(1):33-9

Renault TT, Dejean LM, Manon S. A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2. Mech Ageing Dev. 2017 Jan;161(Pt B):201-210

Beaumatin F, El Dhaybi M, Lasserre JP, Salin B, Moyer MP, Verdier M, Manon S, Priault M. N52 monodeamidated Bcl?xL shows impaired oncogenic properties in vivo and in vitro. Oncotarget. 2016 Mar 29;7(13):17129-43

Seiliez I, Belghit I, Gao Y, Skiba-Cassy S, Dias K, Cluzeaud M, Rémond D, Hafnaoui N, Salin B, Camougrand N, Panserat S. Looking at the metabolic consequences of the colchicine-based in vivo autophagic flux assay. Autophagy. 2016;12(2):343-56

Simonyan L, Renault TT, Novais MJ, Sousa MJ, Côrte-Real M, Camougrand N, Gonzalez C, Manon S. Regulation of Bax/mitochondria interaction by AKT. FEBS Lett. 2016 Jan;590(1):13-21

Teijido O, Ganesan YT, Llanos R, Peton A, Urtecho JB, Soprani A, Villamayor A, Antonsson B, Manon S, Dejean L. A sandwich ELISA for the conformation-specific quantification of the activated form of human Bax. Anal Biochem. 2016 Mar 15;497:90-4

Athané A, Buisson A, Challier M, Beaumatin F, Manon S, Bhatia-Ki??ová I, Camougrand N. Insights into the relationship between the proteasome and autophagy in human and yeast cells. Int J Biochem Cell Biol. 2015 Jul;64:167-73

Renault TT, Teijido O, Missire F, Ganesan YT, Velours G, Arokium H, Beaumatin F, Llanos R, Athané A, Camougrand N, Priault M, Antonsson B, Dejean LM, Manon S. Bcl-xL stimulates Bax relocation to mitochondria and primes cells to ABT-737. Int J Biochem Cell Biol. 2015 Jul;64:136-46

Gabriel F, Accoceberry I, Bessoule JJ, Salin B, Lucas-Guérin M, Manon S, Dementhon K, Noël T. A Fox2-dependent fatty acid ß-oxidation pathway coexists both in peroxisomes and mitochondria of the ascomycete yeast Candida lusitaniae. PLoS One. 2014;9(12):e114531

Alves S, Cormier-Dequaire F, Marinello M, Marais T, Muriel MP, Beaumatin F, Charbonnier-Beaupel F, Tahiri K, Seilhean D, El Hachimi K, Ruberg M, Stevanin G, Barkats M, den Dunnen W, Priault M, Brice A, Durr A, Corvol JC, Sittler A. The autophagy/lysosome pathway is impaired in SCA7 patients and SCA7 knock-in mice. Acta Neuropathol. 2014 Nov;128(5):705-22

Bayot A, Gareil M, Chavatte L, Hamon MP, L'Hermitte-Stead C, Beaumatin F, Priault M, Rustin P, Lombès A, Friguet B, Bulteau AL. Effect of Lon protease knockdown on mitochondrial function in HeLa cells. Biochimie. 2014 May;100:38-47

Bhatia-Ki??ová I, Camougrand N. Mitophagy is not induced by mitochondrial damage but plays a role in the regulation of cellular autophagic activity. Autophagy. 2013 Nov 1;9(11):1897-9

Rego A, Trindade D, Chaves SR, Manon S, Costa V, Sousa MJ, Côrte-Real M. The yeast model system as a tool towards the understanding of apoptosis regulation by sphingolipids. FEMS Yeast Res. 2014 Feb;14(1):160-78

Prudent J, Popgeorgiev N, Bonneau B, Thibaut J, Gadet R, Lopez J, Gonzalo P, Rimokh R, Manon S, Houart C, Herbomel P, Aouacheria A, Gillet G. Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish. Nat Commun. 2013;4:2330

Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, Goorden S, Priault M, Elgersma Y, Rezvani HR, Rossignol R, Bénard G. Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab. 2013 May 7;17(5):719-30

Deffieu M, Bhatia-Ki??ová I, Salin B, Klionsky DJ, Pinson B, Manon S, Camougrand N. Increased levels of reduced cytochrome b and mitophagy components are required to trigger nonspecific autophagy following induced mitochondrial dysfunction. J Cell Sci. 2013 Jan 15;126(Pt 2):415-26

Erjavec N, Bayot A, Gareil M, Camougrand N, Nystrom T, Friguet B, Bulteau AL. Deletion of the mitochondrial Pim1/Lon protease in yeast results in accelerated aging and impairment of the proteasome. Free Radic Biol Med. 2013 Mar;56:9-16

Renault TT, Teijido O, Antonsson B, Dejean LM, Manon S. Regulation of Bax mitochondrial localization by Bcl-2 and Bcl-x(L): keep your friends close but your enemies closer. Int J Biochem Cell Biol. 2013 Jan;45(1):64-7

Bhatia-Ki??ová I, Camougrand N. Mitophagy: a process that adapts to the cell physiology. Int J Biochem Cell Biol. 2013 Jan;45(1):30-3

Oliver L, Hue E, Priault M, Vallette FM. Basal autophagy decreased during the differentiation of human adult mesenchymal stem cells. Stem Cells Dev. 2012 Oct 10;21(15):2779-88

Renault TT, Grandier-Vazeille X, Arokium H, Velours G, Camougrand N, Priault M, Teijido O, Dejean LM, Manon S. The cytosolic domain of human Tom22 modulates human Bax mitochondrial translocation and conformation in yeast. FEBS Lett. 2012 Jan 20;586(2):116-21

Trocoli A, Mathieu J, Priault M, Reiffers J, Souquère S, Pierron G, Besançon F, Djavaheri-Mergny M. ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells. Autophagy. 2011 Oct;7(10):1108-14

Renault TT, Manon S. Bax: Addressed to kill. Biochimie. 2011 Sep;93(9):1379-91

Silva RD, Manon S, Gonçalves J, Saraiva L, Côrte-Real M. The importance of humanized yeast to better understand the role of bcl-2 family in apoptosis: finding of novel therapeutic opportunities. Curr Pharm Des. 2011;17(3):246-55

Gautier F, Guillemin Y, Cartron PF, Gallenne T, Cauquil N, Le Diguarher T, Casara P, Vallette FM, Manon S, Hickman JA, Geneste O, Juin P. Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL. Mol Cell Biol. 2011 Feb;31(4):832-44

Silva RD, Manon S, Gonçalves J, Saraiva L, Côrte-Real M. Modulation of Bax mitochondrial insertion and induced cell death in yeast by mammalian protein kinase C?. Exp Cell Res. 2011 Apr 1;317(6):781-90

Bhatia-Ki??ová I, Camougrand N. Mitophagy in yeast: actors and physiological roles. FEMS Yeast Res. 2010 Dec;10(8):1023-34

Pereira C, Chaves S, Alves S, Salin B, Camougrand N, Manon S, Sousa MJ, Côrte-Real M. Mitochondrial degradation in acetic acid-induced yeast apoptosis: the role of Pep4 and the ADP/ATP carrier. Mol Microbiol. 2010 Jun;76(6):1398-410

Priault M, Hue E, Marhuenda F, Pilet P, Oliver L, Vallette FM. Differential dependence on Beclin 1 for the regulation of pro-survival autophagy by Bcl-2 and Bcl-xL in HCT116 colorectal cancer cells. PLoS One. 2010 Jan 18;5(1):e8755

Kissová IB, Camougrand N. Glutathione participates in the regulation of mitophagy in yeast. Autophagy. 2009 Aug;5(6):872-3

Gallenne T, Gautier F, Oliver L, Hervouet E, Noël B, Hickman JA, Geneste O, Cartron PF, Vallette FM, Manon S, Juin P. Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J Cell Biol. 2009 Apr 20;185(2):279-90

Deffieu M, Bhatia-Kissová I, Salin B, Galinier A, Manon S, Camougrand N. Glutathione participates in the regulation of mitophagy in yeast. J Biol Chem. 2009 May 29;284(22):14828-37