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Accueil > Départements > Biologie Cellulaire > Agnès DELAHODDE : Fonctions et Dysfonctions des Mitochondries



  • S. Ait-El-Mkadem, M. Dayem-Quere, M. Gusic, A. Chaussenot, S. Bannwarth, B. François, E. C. Genin, K. Fragaki, C. L. M. Volker-Touw, C. Vasnier, V. Serre, K. L. I. van Gassen, F. Lespinasse, S. Richter, G. Eisenhofer, C. Rouzier, F. Mochel, A. De Saint-Martin, M. - T. Abi Warde, M. G. M. de Sain-van der Velde, J. J. M. Jans, J. Amiel, Z. Avsec, C. Mertes, T. B. Haack, T. Strom, T. Meitinger, P. E. Bonnen, R. W. Taylor, J. Gagneur, P. M. van Hasselt, A. Rötig, A. Delahodde, H. Prokisch, S. A. Fuchs, et V. Paquis-Flucklinger, « Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy », American Journal of Human Genetics, vol. 100, nᵒ 1, p. 151-159, 2017.

  • F. Habarou, Y. Hamel, T. B. Haack, R. G. Feichtinger, E. Lebigot, I. Marquardt, K. Busiah, C. Laroche, M. Madrange, C. Grisel, C. Pontoizeau, M. Eisermann, A. Boutron, D. Chrétien, B. Chadefaux-Vekemans, R. Barouki, C. Bole-Feysot, P. Nitschke, N. Goudin, N. Boddaert, I. Nemazanyy, A. Delahodde, S. Kölker, R. J. Rodenburg, G. C. Korenke, T. Meitinger, T. M. Strom, H. Prokisch, A. Rotig, C. Ottolenghi, J. A. Mayr, et P. de Lonlay, « Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy », American Journal of Human Genetics, vol. 101, nᵒ 2, p. 283-290, août 2017.
    Résumé : Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.
    Mots-clés : BIOCELL, encephalopathy, FDMITO, hyperglycinemia, lipoic acid, LIPT2, metabolic flux, pyruvate dehydrogenase, α-oxoglutarate dehydrogenase.

  • C. Panozzo, A. Laleve, D. Tribouillard-Tanvier, J. Ostojić, C. Sellem, G. Friocourt, A. Bourand-Plantefol, A. Burg, A. Delahodde, M. Blondel, et G. Dujardin, « Chemicals or mutations that target mitochondrial translation can rescue the respiratory deficiency of yeast bcs1 mutants », Biochimica Et Biophysica Acta, sept. 2017.
    Résumé : Bcs1p is a chaperone that is required for the incorporation of the Rieske subunit within complex III of the mitochondrial respiratory chain. Mutations in the human gene BCS1L (BCS1-like) are the most frequent nuclear mutations resulting in complex III-related pathologies. In yeast, the mimicking of some pathogenic mutations causes a respiratory deficiency. We have screened chemical libraries and found that two antibiotics, pentamidine and clarithromycin, can compensate two bcs1 point mutations in yeast, one of which is the equivalent of a mutation found in a human patient. As both antibiotics target the large mtrRNA of the mitoribosome, we focused our analysis on mitochondrial translation. We found that the absence of non-essential translation factors Rrf1 or Mif3, which act at the recycling/initiation steps, also compensates for the respiratory deficiency of yeast bcs1 mutations. At compensating concentrations, both antibiotics, as well as the absence of Rrf1, cause an imbalanced synthesis of respiratory subunits which impairs the assembly of the respiratory complexes and especially that of complex IV. Finally, we show that pentamidine also decreases the assembly of complex I in nematode mitochondria. It is well known that complexes III and IV exist within the mitochondrial inner membrane as supramolecular complexes III2/IV in yeast or I/III2/IV in higher eukaryotes. Therefore, we propose that the changes in mitochondrial translation caused by the drugs or by the absence of translation factors, can compensate for bcs1 mutations by modifying the equilibrium between illegitimate, and thus inactive, and active supercomplexes.
    Mots-clés : Antibiotics, Bcs1 protein, BIOCELL, BIOMIT, FDMITO, mitochondria, Respiratory chain, translation, Yeast.

  • A. Paul, A. Drecourt, F. Petit, D. D. Deguine, C. Vasnier, M. Oufadem, C. Masson, C. Bonnet, S. Masmoudi, I. Mosnier, L. Mahieu, D. Bouccara, J. Kaplan, G. Challe, C. Domange, F. Mochel, O. Sterkers, S. Gerber, P. Nitschke, C. Bole-Feysot, L. Jonard, S. Gherbi, O. Mercati, I. Ben Aissa, S. Lyonnet, A. Rötig, A. Delahodde, et S. Marlin, « FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases », American Journal of Human Genetics, sept. 2017.
    Résumé : Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.
    Mots-clés : ARH1, Auditory neuropathy, BIOCELL, FDMITO, FDXR, Fe-S cluster synthesis, iron overload, iron-sulfur cluster, mitochondria, optic atrophy.


  • M. G. Addo, R. Cossard, D. Pichard, K. Obiri Danso, A. R ouml tig, et A. Delahodde, « Investigation of yeast genes possibly involved in mtDNA stability using the nematode Caenorhabditis elegans », African Journal of Biotechnology, vol. 15, nᵒ 22, p. 1008-1014, juin 2016.

  • M. G. Addo, R. Cossard, D. Pichard, K. Obiri- Danso, A. Rötig, et A. Delahodde, « Identification of New Genes Involved in mtDNA Maintenance in Caenorhabditis elegans that could Represent Candidate Genes for Mitochondrial Diseases », International Journal of Current Microbiology and Applied Sciences, vol. 5, nᵒ 6, p. 179-189, juin 2016.

  • A. Guimier, C.  T. Gordon, F. Godard, G. Ravenscroft, M. Oufadem, C. Vasnier, C. Rambaud, P. Nitschke, C. Bole-Feysot, C. Masson, S. Dauger, C. Longman, N.  G. Laing, B. Kugener, D. Bonnet, P. Bouvagnet, S. Di Filippo, V. Probst, R. Redon, P. Charron, A. Rötig, S. Lyonnet, A. Dautant, L. de Pontual, J. - P. di Rago, A. Delahodde, et J. Amiel, « Biallelic PPA2 Mutations Cause Sudden Unexpected Cardiac Arrest in Infancy », American Journal of Human Genetics, vol. 99, nᵒ 3, p. 666-673, 2016.

  • L. Pitayu, E. Baruffini, C. Rodier, A. Rötig, T. Lodi, et A. Delahodde, « Combined use of Saccharomyces cerevisiae, Caenorhabditis elegans and patient fibroblasts leads to the identification of clofilium tosylate as a potential therapeutic chemical against POLG-related diseases », Human Molecular Genetics, vol. 25, nᵒ 4, p. 715-727, févr. 2016.
    Résumé : Mitochondria are organelles that have their own DNA (mitochondrial DNA, mtDNA) whose maintenance is necessary for the majority of ATP production in eukaryotic cells. Defects in mtDNA maintenance or integrity are responsible for numerous diseases. The DNA polymerase γ (POLG) ensures proper mtDNA replication and repair. Mutations in POLG are a major cause of mitochondrial disorders including hepatic insufficiency, Alpers syndrome, progressive external ophthalmoplegia, sensory neuropathy and ataxia. Mutations in POLG are also associated with parkinsonism. To date, no effective therapy is available. Based on the conservation of mitochondrial function from yeast to human, we used Saccharomyces cerevisiae and Caenorhabditis elegans as first pass filters to identify a chemical that suppresses mtDNA instability in cultured fibroblasts of a POLG-deficient patient. We showed that this unsuspected compound, clofilium tosylate (CLO), belonging to a class of anti-arrhythmic agents, prevents mtDNA loss of all yeast mitochondrial polymerase mutants tested, improves behavior and mtDNA content of polg-1-deficient worms and increases mtDNA content of quiescent POLG-deficient fibroblasts. Furthermore, the mode of action of the drug seems conserved as CLO increases POLG steady-state level in yeast and human cells. Two other anti-arrhythmic agents (FDA-approved) sharing common pharmacological properties and chemical structure also show potential benefit for POLG deficiency in C. elegans. Our findings provide evidence of the first mtDNA-stabilizing compound that may be an effective pharmacological alternative for the treatment of POLG-related diseases.
    Mots-clés : Animals, BIOCELL, Caenorhabditis elegans, DNA Polymerase I, DNA replication, DNA, Mitochondrial, DNA-Directed DNA Polymerase, FDMITO, Fibroblasts, Humans, Mitochondrial Diseases, Mutation, Phenotype, Primary Cell Culture, Quaternary Ammonium Compounds, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins.

  • C. H. Sellem, J. - P. di Rago, J. - P. Lasserre, S. H. Ackerman, et A. Sainsard-Chanet, « Regulation of Aerobic Energy Metabolism in Podospora anserina by Two Paralogous Genes Encoding Structurally Different c-Subunits of ATP Synthase », PLOS Genetics, vol. 12, nᵒ 7, p. e1006161, juill. 2016.


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- Saunier R, Esposito M, Dassa EP, Delahodde A (2013) Integrity of the Saccharomyces cerevisiae Rpn11 protein is critical for formation of proteasome storage granules (PSG) and survival in stationary phase. PLoS One Aug 6 ;8(8):e70357 Biochim Biophys Acta - Molecular Basis of Disease 1802 (2013), pp. 765-773
- Adam C, Picard M, Déquard-Chablat M, Sellem CH, Hermann-Le Denmat S, Contamine V (2012) Biological Roles of the Podospora anserina Mitochondrial Lon Protease and the Importance of its N-Domain. PLoS One 7 : e38138
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- Bietenhader M, Martos A, Tetaud E, Aiyar RS, Sellem CH (7 authors), Déquard-Chablat M, Contamine V , Hermann-Le Denmat S, Sainsard-Chanet A, Steinmetz LM, di Rago JP (2012) Experimental Relocation of the Mitochondrial ATP9 Gene to the Nucleus Reveals Forces Underlying Mitochondrial Genome Evolution. PLoS Genet 8 : e1002876
- Galopier A, Hermann-Le Denmat S (2011) Mitochondria of the Yeasts Saccharomyces cerevisiae and Kluyveromyces lactis Contain Nuclear rDNA-Encoded Proteins. PLoS One 6 : e16325
- 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 (2011) Two nuclear life-cycle-regulated genes encode interchangeable subunits c of mitochondrial ATP synthase in Podospora anserina. Mol Biol Evol 28 : 2063-2075
- Addo MG, Cossard R, Pichard D, Obiri-Danso K, Rotig A, Delahodde A (2010) Caenorhabditis elegans, a pluricellular model organism to screen new genes involved in mitochondrial genome maintenance. Biochim Biophys Acta-Molecular basis of disease 1802 : 765-773
- Hofmann L, Saunier R, Cossard R, Esposito M, Rinaldi T, Delahodde A (2009) A nonproteolytic proteasome activity controls organelle fission in yeast. J Cell Sci 122 : 3673-3683. Editor’s Choice (2009) JCS « Keeping a lid on organelle fission » J Cell Sci 122 : e2002.
- Rinaldi T, Hofmann L, Gambadoro A, Cossard R, Livnat-Levanon N, Glickman MH, Delahodde A (2008) Dissection of the carboxyl-terminal domain of the proteasomal subunit Rpn11 in maintenance of mitochondrial structure and function. Mol Biol Cell 19 : 1022-1031
- Gonzales F, Delahodde A, Kodadek T and Johnston S.A. Recruitment of a 19S proteasome subcomplex to an activated promoter. Science. (2002) 296(5567) : 548-550

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