Research > Team Molecular Genetics of Mitochondrial Systems

Molecular Genetics of Mitochondrial Systems

Principal Investigator : Jean-Paul di Rago


Team Members

Alain Dautant - CRHC CNRS

Jean-Paul di Rago - DR2 CNRS

François Godard - AI CNRS

Kewin Gombeau - Post-Doc CRA

Xin Su - Doctorante Bourse Franco-Chinoise

Deborah Tribouillard-Tanvier - CRCN INSERM


Former Team Members

Alexandre Martos - PhD ANR (2009-12) Rak Malgorzata - PhD Rétina/AFM/Pologne (2004-07)
Bietenhader Maïlis - PhD BDI (2007-09) Ezcurdia Nahia - Ingénieur ANR (2005-07)
Laclau Muriel - Post-Doc CRA (2009) Schwimmer Christine - Post-Doc Rétina/AFM (2003-05)
Kucharczyk Roza Post-Doc ANR (2006-08) Caron Matthieu - Technicien (2003)
Zick Michael - PhD EMBO (2008) Lefebvre-Legendre Linnka - PhD MRT (1999-01)




Our work is mainly devoted to the study of the mitochondrial ATP synthase, its biogenesis, regulation, evolution and implication in human diseases. This enzyme provides aerobic eukaryotes with most of their ATP requirements through the process of oxidative phosphorylation. The ATP synthase utilizes the energy of an electrochemical potential (ΔµH) across the inner mitochondrial membrane (IMM), which is maintained by a series of respiratory complexes (I-IV) that couple the transfer to oxygen of reduced equivalents deriving from fuel molecules (monosaccharides, fatty acids) to proton pumping across the IMM.


Research Activity

Our research is divided into several interconnected axes:

1) The mitochondrial ATP synthase is made of about twenty different subunits of dual genetic origin, nuclear and mitochondrial. Our work is mainly devoted to the study of the biogenesis of the mitochondrial ATP synthase in yeast (Saccharomyces cerevisiae) and human cells. To this end, we have designed genetic and biochemical strategies to identify novel factors involved in the biogenesis of this complex.


2) Cells adapt the energy supply to the cellular demand and this adjustment becomes vital in metabolic diseases such as mitochondrial diseases as well as in diabetes, heart failure, cancer or neurodegenerative diseases where mitochondria are deficient. Our research aims to identify the molecular mechanisms involved in the maintenance of energy transduction in yeast models of mitochondrial diseases. The study of the adaptive response to metabolic stress also includes the study of cellular compensatory responses, such as the activation of mitochondrial biogenesis, and the search for pharmacological agents capable of stimulating mitochondria.


3) Mitochondrial genomes are supposedly derived from the genome of a prokaryotic ancestor. The size of this genome has been drastically reduced during evolution towards eukaryotic cells, mainly explained by a massive gene transfer to the nucleus. Why a mitochondrial genome is maintained after two billions years of evolution is not well understood. We are using yeast as a model to better understand the prerequisites and adaptations required for a relocation of mitochondrial genes to the nucleus.


4) We have also generated yeast models of human disorders associated with ATP synthase defects. We are exploiting these models to screen for drugs that may help finding a cure for these diseases. We have now started to apply this approach to other disorders of mitochondrial origin that can be modeled in yeast.


Expertise & Techniques


Key and active collaborations


Fundings 2009-2014





Mitochondria - ATP synthase - Biogenesis - Mitochondrial genome - Mitochondrial diseases - Drug screening - Evolution - Proteomics


Selected publications 2009-2018

Dautant A, Meier T, Hahn A, Tribouillard-Tanvier D, di Rago JP, Kucharczyk R. ATP Synthase Diseases of Mitochondrial Genetic Origin. Front Physiol. 2018;9:329

Kucharczyk R, Dautant A, Godard F, Tribouillard-Tanvier D, di Rago JP. Functional investigation of an universally conserved leucine residue in subunit a of ATP synthase targeted by the pathogenic m.9176?T>G mutation. Biochim Biophys Acta Bioenerg. 2019 Jan;1860(1):52-59

Carraro M, Checchetto V, Sartori G, Kucharczyk R, di Rago JP, Minervini G, Franchin C, Arrigoni G, Giorgio V, Petronilli V, Tosatto SCE, Lippe G, Szabó I, Bernardi P. High-Conductance Channel Formation in Yeast Mitochondria is Mediated by F-ATP Synthase e and g Subunits. Cell Physiol Biochem. 2018;50(5):1840-1855

de Taffin de Tilques M, Lasserre JP, Godard F, Sardin E, Bouhier M, Le Guedard M, Kucharczyk R, Petit PX, Testet E, di Rago JP, Tribouillard-Tanvier D. Decreasing cytosolic translation is beneficial to yeast and human Tafazzin-deficient cells. Microb Cell. 2018 Feb 18;5(5):220-232

Skocze? N, Dautant A, Binko K, Godard F, Bouhier M, Su X, Lasserre JP, Giraud MF, Tribouillard-Tanvier D, Chen H, di Rago JP, Kucharczyk R. Molecular basis of diseases caused by the mtDNA mutation m.8969G>A in the subunit a of ATP synthase. Biochim Biophys Acta Bioenerg. 2018 Aug;1859(8):602-611

de Taffin de Tilques M, Tribouillard-Tanvier D, Tétaud E, Testet E, di Rago JP, Lasserre JP. Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of Barth syndrome. Dis Model Mech. 2017 Apr 1;10(4):439-450

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

Guimier A, Gordon CT, Godard F, Ravenscroft G, Oufadem M, Vasnier C, Rambaud C, Nitschke P, Bole-Feysot C, Masson C, Dauger S, Longman C, Laing NG, Kugener B, Bonnet D, Bouvagnet P, Di Filippo S, Probst V, Redon R, Charron P, Rötig A, Lyonnet S, Dautant A, de Pontual L, di Rago JP, Delahodde A, Amiel J. Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy. Am J Hum Genet. 2016 Sep 1;99(3):666-673

Aaltonen MJ, Friedman JR, Osman C, Salin B, di Rago JP, Nunnari J, Langer T, Tatsuta T. MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. J Cell Biol. 2016 Jun 6;213(5):525-34

Niedzwiecka K, Kabala AM, Lasserre JP, Tribouillard-Tanvier D, Golik P, Dautant A, di Rago JP, Kucharczyk R. Yeast models of mutations in the mitochondrial ATP6 gene found in human cancer cells. Mitochondrion. 2016 Jul;29:7-17

Sellem CH, di Rago JP, Lasserre JP, Ackerman SH, Sainsard-Chanet A. Regulation of Aerobic Energy Metabolism in Podospora anserina by Two Paralogous Genes Encoding Structurally Different c-Subunits of ATP Synthase. PLoS Genet. 2016 Jul;12(7):e1006161

Lasserre JP, Dautant A, Aiyar RS, Kucharczyk R, Glatigny A, Tribouillard-Tanvier D, Rytka J, Blondel M, Skoczen N, Reynier P, Pitayu L, Rötig A, Delahodde A, Steinmetz LM, Dujardin G, Procaccio V, di Rago JP. Yeast as a system for modeling mitochondrial disease mechanisms and discovering therapies. Dis Model Mech. 2015 Jun;8(6):509-26

Sardin E, Donadello S, di Rago JP, Tetaud E. Biochemical investigation of a human pathogenic mutation in the nuclear ATP5E gene using yeast as a model. Front Genet. 2015;6:159

Aiyar RS, Bohnert M, Duvezin-Caubet S, Voisset C, Gagneur J, Fritsch ES, Couplan E, von der Malsburg K, Funaya C, Soubigou F, Courtin F, Suresh S, Kucharczyk R, Evrard J, Antony C, St Onge RP, Blondel M, di Rago JP, van der Laan M, Steinmetz LM. Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders. Nat Commun. 2014 Dec 18;5:5585

Frechin M, Enkler L, Tetaud E, Laporte D, Senger B, Blancard C, Hammann P, Bader G, Clauder-Münster S, Steinmetz LM, Martin RP, di Rago JP, Becker HD. Expression of nuclear and mitochondrial genes encoding ATP synthase is synchronized by disassembly of a multisynthetase complex. Mol Cell. 2014 Dec 18;56(6):763-76

Wu Q, Andrianaivomananjaona T, Tetaud E, Corvest V, Haraux F. Interactions involved in grasping and locking of the inhibitory peptide IF1 by mitochondrial ATP synthase. Biochim Biophys Acta. 2014 Jun;1837(6):761-72

Ostojić J., di Rago J.-P. and Dujardin G. (2014). A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation Microbial Cell 1, 43-44

Tetaud E, Godard F, Giraud MF, Ackerman SH, di Rago JP. The depletion of F1 subunit ε in yeast leads to an uncoupled respiratory phenotype that is rescued by mutations in the proton-translocating subunits of F0 Mol Biol Cell. 2014 Mar;25(6):791-9

Jimenez L, Laporte D, Duvezin-Caubet S, Courtout F, Sagot I. Mitochondrial ATP synthases cluster as discrete domains that reorganize with the cellular demand for oxidative phosphorylation. J Cell Sci. 2014 Feb 15;127(Pt 4):719-26

Kabala AM, Lasserre JP, Ackerman SH, di Rago JP, Kucharczyk R. Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C. Biochimie. 2014 May;100:200-6

Lefebvre M, Tetaud E, Thonnus M, Salin B, Boissier F, Blancard C, Sauvanet C, Metzler C, Espiau B, Sahin A, Merlin G. LdFlabarin, a new BAR domain membrane protein of Leishmania flagellum. PLoS One. 2013;8(9):e76380

Ostojić J, Panozzo C, Lasserre JP, Nouet C, Courtin F, Blancard C, di Rago JP, Dujardin G. The energetic state of mitochondria modulates complex III biogenesis through the ATP-dependent activity of Bcs1 Cell Metab. 2013 Oct 1;18(4):567-77

Sauvanet C, Duvezin-Caubet S, Salin B, David C, Massoni-Laporte A, di Rago JP, Rojo M. Mitochondrial DNA mutations provoke dominant inhibition of mitochondrial inner membrane fusion. PLoS One. 2012;7(11):e49639

Frank M, Duvezin-Caubet S, Koob S, Occhipinti A, Jagasia R, Petcherski A, Ruonala MO, Priault M, Salin B, Reichert AS. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta. 2012 Dec;1823(12):2297-310

Bietenhader M, Martos A, Tetaud E, Aiyar RS, Sellem CH, Kucharczyk R, Clauder-Münster S, Giraud MF, Godard F, Salin B, Sagot I, Gagneur J, Déquard-Chablat M, Contamine V, Hermann-Le Denmat S, Sainsard-Chanet A, Steinmetz LM, di Rago JP. Experimental relocation of the mitochondrial ATP9 gene to the nucleus reveals forces underlying mitochondrial genome evolution. PLoS Genet. 2012;8(8):e1002876

Kucharczyk R, Giraud MF, Brèthes D, Wysocka-Kapcinska M, Ezkurdia N, Salin B, Velours J, Camougrand N, Haraux F, di Rago JP. Defining the pathogenesis of human mtDNA mutations using a yeast model: the case of T8851C. Int J Biochem Cell Biol. 2013 Jan;45(1):130-40

Couplan E, Aiyar RS, Kucharczyk R, Kabala A, Ezkurdia N, Gagneur J, St Onge RP, Salin B, Soubigou F, Le Cann M, Steinmetz LM, di Rago JP, Blondel M. A yeast-based assay identifies drugs active against human mitochondrial disorders. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11989-94

Godard F, Tetaud E, Duvezin-Caubet S, di Rago JP. A genetic screen targeted on the FO component of mitochondrial ATP synthase in Saccharomyces cerevisiae. J Biol Chem. 2011 May 20;286(20):18181-9

Déquard-Chablat M, Sellem CH, Golik P, Bidard F, Martos A, Bietenhader M, di Rago JP, Sainsard-Chanet A, Hermann-Le Denmat S, Contamine V. Two nuclear life cycle-regulated genes encode interchangeable subunits c of mitochondrial ATP synthase in Podospora anserina. Mol Biol Evol. 2011 Jul;28(7):2063-75

Schäfer A, Zick M, Kief J, Steger M, Heide H, Duvezin-Caubet S, Neupert W, Reichert AS. Intramembrane proteolysis of Mgm1 by the mitochondrial rhomboid protease is highly promiscuous regarding the sequence of the cleaved hydrophobic segment. J Mol Biol. 2010 Aug 13;401(2):182-93

Kucharczyk R, Ezkurdia N, Couplan E, Procaccio V, Ackerman SH, Blondel M, di Rago JP. Consequences of the pathogenic T9176C mutation of human mitochondrial DNA on yeast mitochondrial ATP synthase. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1105-12

Sauvanet C, Duvezin-Caubet S, di Rago JP, Rojo M. Energetic requirements and bioenergetic modulation of mitochondrial morphology and dynamics. Semin Cell Dev Biol. 2010 Aug;21(6):558-65

Meulemans A, Seneca S, Pribyl T, Smet J, Alderweirldt V, Waeytens A, Lissens W, Van Coster R, De Meirleir L, di Rago JP, Gatti DL, Ackerman SH. Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model. J Biol Chem. 2010 Feb 5;285(6):4099-4109

Zick M, Duvezin-Caubet S, Schäfer A, Vogel F, Neupert W, Reichert AS. Distinct roles of the two isoforms of the dynamin-like GTPase Mgm1 in mitochondrial fusion. FEBS Lett. 2009 Jul 7;583(13):2237-43

Kucharczyk R, Salin B, di Rago JP. Introducing the human Leigh syndrome mutation T9176G into Saccharomyces cerevisiae mitochondrial DNA leads to severe defects in the incorporation of Atp6p into the ATP synthase and in the mitochondrial morphology. Hum Mol Genet. 2009 Aug 1;18(15):2889-98

Ding MG, Butler CA, Saracco SA, Fox TD, Godard F, di Rago JP, Trumpower BL. Chapter 27 An improved method for introducing point mutations into the mitochondrial cytochrome B gene to facilitate studying the role of cytochrome B in the formation of reactive oxygen species. Methods Enzymol. 2009;456:491-506

Kucharczyk R, Rak M, di Rago JP. Biochemical consequences in yeast of the human mitochondrial DNA 8993T>C mutation in the ATPase6 gene found in NARP/MILS patients. Biochim Biophys Acta. 2009 May;1793(5):817-24

Ding MG, di Rago JP, Trumpower BL. Combining Inhibitor Resistance-conferring Mutations in Cytochrome b Creates Conditional Synthetic Lethality in Saccharomyces cerevisiae. J Biol Chem. 2009 Mar 27;284(13):8478-85

Kucharczyk R, Zick M, Bietenhader M, Rak M, Couplan E, Blondel M, Caubet SD, di Rago JP. Mitochondrial ATP synthase disorders: molecular mechanisms and the quest for curative therapeutic approaches. Biochim Biophys Acta. 2009 Jan;1793(1):186-99



Une nouvelle cible thérapeutique pour réparer la centrale énergétique cellulaire. Un grand nombre de mutations affectent les machineries, dont l'ATP synthase, impliquées dans la production d'énergie sous forme d'ATP par les mitochondries. Elles entraînent des maladies métaboliques et neuromusculaires pour lesquelles il n'existe aucun traitement efficace. Un groupement international pluridisciplinaire, incluant l'équipe de Jean-Paul di Rago à l'Institut de biochimie et génétique cellulaires, a identifié le complexe TIM23, responsable de l'import et du tri dans les mitochondries des protéines issues de gènes nucléaires, comme une nouvelle cible pour le traitement de ces maladies. La modulation génétique ou chimique de TIM23 permet d'améliorer le fonctionnement de mitochondries dont l'ATP synthase est défectueuse. Cette étude est publiée dans la revue Nature Communications.
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Un mécanisme inédit de synchronisation de l'expression des génomes nucléaire et mitochondrial. La production d'énergie par la chaîne respiratoire des mitochondries nécessite un assemblage correct de sous-unités protéiques codées séparément par les génomes nucléaire et mitochondrial qui entretiennent un véritable "dialogue" assurant la synchronisation de l'expression de ces protéines. Les équipes d'Hubert Becker à l'IPCB (Strasbourg) et de Jean-Paul di Rago à l'IBGC (Bordeaux), révèlent le rôle central dans ce processus du complexe AME de S. cerevisiae composé de deux aminoacyl-ARNt synthétases et d'une ancre cytoplasmique. Cette étude est publiée dans la revue Molecular Cell.
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La levure de boulanger est un nouvel outil pour mieux comprendre les pathologies mitochondriales. En effet des chercheurs du CNRS, de l'Inserm et des Universités Bordeaux Segalen et Bretagne Occidentale à Brest ont montré que la levure peut mimer les déficiences mitochondriales et servir ainsi de support dans la recherche de pistes thérapeutiques. Les résultats de ces travaux ont été publiés dans la revue PNAS.
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Saccharomyces cerevisiae validée comme modèle pharmacologique pour l'étude de maladies mitochondriales. Les équipes CNRS UMR 5095 de Jean-Paul di Rago à Bordeaux et Inserm U613 de Marc Blondel à Brest développent un système basé sur la levure pour rechercher des molécules actives contre des déficiences mitochondriales, responsables de maladies humaines. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11989-94.
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Trophée INPI de l'Innovation 2008 Aquitaine. L'équipe de Jean-Paul di Rago récompensée. Les Trophées INPI de l'Innovation distinguent des PME, ainsi que des organismes de recherche et laboratoires pour leur capacité à valoriser leur recherche et développement grâce à la propriété industrielle
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