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    Pathophysiology of inherited defects of mitochondrial oxidative phosphorylation

    Principal investigator : Anne Lombès

    Contact : – Phone : +33 1 53 73 27 51


    Upper panel: from left to right: coupled cytochrome c oxidase (COX) and succinate dehydrogenase histochemistry of a muscle section from a patient showing scattered muscle fibers with COX defect appearing in blue while fibers with normal COX activity are in brown; immunohistochemical reaction for the mitochondrial DNA-encoded subunit 2 of cytochrome c oxidase with an antibody produced in the team showing the mitochondrial morphology of cultured fibroblasts with OPA1 mutations.

    Lower panel: analysis of the respiration in the striata from a single mouse using high resolution respirometry in Oroboros apparatus.




    Inherited mitochondrial diseases, defined as the diseases due to an OXHOS defect, have an estimated prevalence of 1/5000 individuals. They have very diverse clinical presentations in accordance to their multiple causes with gene mutations located either in the mitochondrial or nuclear genome. Our main objective is to address the pathophysiological mechanisms of mitochondrial diseases to understand the extreme phenotypic diversity of these diseases and to find potential therapeutic avenues.

    The group

    Karine Auré, MCU-PH AP-HP researcher, Claude Jardel, PH AP-HP researcher, Caroline L’hermitte-Stead, lab assistant, and Nathalie Le Foll, PhD student (in co-supervision with Pr Wolf) are involved in the project.


    Research interests


    We have a strong interest in clinical research, in particular in genotype/phenotype relationship. Within that interest we recently showed that diseases due to defective mitochondrial DNA maintenance related to mutations of either POLG or TK2 nuclear genes presented with a reproducible set of signs/symptoms but that their rate of progression could considerably vary from early onset rapidly lethal cases to late onset slowly progressive diseases (Tchikviladze 2015, Neeve 2012, Béhin 2012). The search for the underlying genetic modifying factors is undertaken within an international collaboration.

    Our second main interest resides in the molecular mechanisms of mitochondrial diseases that we most often analyze in cells derived from patients. We deciphered the mitochondrial consequences of OPA1 mutations associated with autosomal dominant optic atrophy (Agier 2012) and identified a new cause for severe congenital lactic acidosis with cytochrome c oxidase defect (Weraarpachai 2012).

    We recently described that mutations of mitochondrial DNA genes encoding subunits of the ATP synthase (complex V of the OXPHOS pathway) were responsible for an original phenotype associating recurrent accesses of paralysis and progressive degeneration of motor neurons (Auré et al Neurology 2013). Permanent depolarization of cultured fibroblasts plasma membrane provided a molecular substratum for the accesses of paralysis while bioenergetic consequences of the complex V defect essentially impacted the metabolism of reactive oxygen species. The molecular mechanisms associated with these particular mutations are addressed in different cellular models including fibroblasts, cybrids and neuronal precursor cells derived from induced pluripotent stem cells obtained from the patients’ fibroblasts.



    Left panel: increased superoxide anion production in the patients’ fibroblasts; right panel: decreased plasma membrane potential in the patients’ fibroblasts.


    Main publications


    18-1 Le Guillou D, Bucher S, Begriche K, Hoët D, Lombès A,Labbe G, Fromenty B. Drug-induced alterations of mitochondrial DNA homeostasis in steatotic and non-steatotic HepaRG cells. Journal of Pharmacology and Experimental Therapeutics 2018 365(3):711-726

    18-2 Repp BM, Mastantuono E, Alston CL, Schiff M, Haack T, Rötig A, Ardissone A, Lombès A, Catarino C, Diodato D, Schottmann G, Poulton J, Burlina A, Jonckheere A, Munnich A, Rolinski B, Ghezzi D, Rokicki D, Wellesley D, Martinelli D, Wenhong D, Lamantea E, Ostergaard E, Pronicka E, Pierre G, Smeets HJM, Wittig I, Scurr I, de Coo IFM, Moroni I, Smet J, Mayr JA, Dai L, de Meirleir L, Schuelke M, Zeviani M, Morscher RJ, McFarland R, Seneca S, Klopstock T, Meitinger T, Wieland T, Strom T, Herberg U, Ahting U, Sperl W, Nassogne MC, Ling H, Fang F, Freisinger P, Van Coster R, Strecker V, Taylor RW, Häberle J, Vockley J, Prokisch H, Wortmann SB. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective? Orphanet Journal of Rare Diseases 2018 13(1):120

    18-3 Iommarini L, Ghell A, Tropeano CV, Kurelac I, Leone G, Vidoni S, Lombès A, Zeviani M, Gasparre G and Porcelli AM.  Int J Mol Sci 2018 19(3) pii: E76419(3)

    18-2 Arena G, Pyrdziak S,Riscal R, Angebault-Prouteau C,Chatre L,Cissé MY, Gayte L, Chabi B, Fuentes M, Bertrand-Gaday C, Vincent C, Bernex F, Casas F, Marine JC, LombèsA, Dubouchaud H, Ricchetti M, Linares LK, Le Cam L. Mitochondrial MDM2 regulates complex I activity independently of p53. Mol Cell 2018 69(4):594-60 

    18-1 TouatM, Sourisseau T, Dorvault N, Merial Chabanon R, Garrido M, Morel D, Krastev DB, Bigot L, Adam J, Frankum J, Durand S, Pontoizeau C, Souquère S, Kuo MS, Sauvaigo S, Mardakheh F, Sarasin A, Olaussen KA, Friboulet L, Bouillaud F, Pierron G, Ashworth A, Lombès A, Lord CJ, Soria JC, Postel-Vinay S. DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade. JCI 2018 128(4):1671-1687

    17-08 Hescot S, Amazit L, Lhomme M, Travers S, DuBow A, Battini S, Namer IJ, Lombès A, Kontush A, Imperiale A, Baudin E, Lombès M. Mitochondria-associated Membranes are the Intracellular Target of Mitotane: Metabolomic and Lipidomic Approaches. Oncotarget 2017 8(66):109924-109940

    17-07 Kremer LS, Bader DM, Mertes C, Kopajtich R,  Pichler G, Iuso A, Haack TB, Graf E, Schwarzmayr T, Terrile C, Koňaříková E, Repp B, Kastenmüller G, Adamski J, Lichtner P, Leonhardt C, Funalot B, Donati A, Tiranti V, Lombès A, Jardel C, Gläser D, Taylor RW, Ghezzi D, Mayr JA, Rötig A, Freisinger P, Distelmaier F, Strom TM, Meitinger T, Gagneur J, Prokisch H, Genetic diagnosis of Mendelian disorders via RNA sequencing. Nature Comm 2017 8:1582

    17-06 Desai R, Frazier AE, Durigon R, Patel H, Jones AW, Dalla Rosa I, Lake NJ, Compton AG, Mountford HS, Tucker EJ, Mitchell ALR, Jackson D, Sesay A, Di Re M, van den Heuvel LP, Burke D, Francis D, Lunke S, McGillivray G, Mandelstam S, Mochel F, Keren B, Jardel C, Turner AM, Andrews I, Smeitink J, Spelbrink JN, Heales SJ, Kohda M, Ohtake A, Murayama K, Okazaki Y, Lombès A, Holt IJ, Thorburn DR, Spinazzola A. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain 2017 140(6):1595-1610

    17-05 Karaa A, Rahman S, Lombès A, Yu-Wai-Man P, Sheikh MK, Alai-Hansen S, Cohen BH, Dimmock D, Emrick L, Falk MJ, McCormack S, Mirsky D, Moore T, Parikh S, Shoffner J, Taivassalo T, Tarnopolsky M, Tein I, Odenkirchen JC, Goldstein A, on behalf of the Mito Working Group Member Participants. J Inher Metab Dis 2017 40(3):403-414

    17-04 Haidar M, Lombès A, Bouillaud F, Kennedy EJ, Langsley G. HK2 recruitment to phospho-BAD prevents its degradation promoting Warburg glycolysis by Theileria-transformed leukocytes. ACS Infect Dis. 2017 3(3):216-224

    17-03 Gueguen A, Jardel C, Polivka M, Tan SV, Gray F, Vignal C, Lombès A, Gout O, Bostock H (2017). Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia. Clin Neurophysiol. 2017 128(7):1258-1263

    17-02 Fayssoil A, Laforêt P, Bougouin W, Jardel C, Lombès A, Bécane HM, Berber N, Stojkovic T, Béhin A, Eymard B, Duboc D, Wahbi K. Prediction of long-term prognosis by heteroplasmy levels of the m.3243A>G mutation in patients with the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome. Eur J Neurol. 2017 24(2):255-261

    17-01 LorenzC*, Lesimple P*, Bukowiecki R, Zink A, Inak G, Mlody B, Singh M, Semtner M, Mah N, Auré K, Leong M, Zabiegalov O, Lyras EM, Pfiffer V, Fauler B, Eichhorst J, Wiesner B, Huebner N, Priller J, Mielke T, Meierhofer D, Izsvák Z, Meier JC, Bouillaud F, Adjaye J, Schuelke M, Wanker EE, Lombès A§, Prigione A§. Human iPSC-derived progenitors are an effective drug discovery model for neurological mitochondrial DNA disorders. Cell Stem Cell 2017 20(5):659-674

    16-02 Guarani V*, Jardel C*, Chrétien D, Lombès A, Labasse C, Lacène E, Bourillon A, Imbard A, Benoist J.F., GoetzmanE.S., Slama A, Elmaleh-Bergès M, Romero NB, Rustin P, Ogier de Baulny H, Harper W, Schiff M.QIL1 mutation cause early onset fatal mitochondrial encephalopathy with recurrent liver failure and MICOS disassembly. eLife 2016 e17163

    16-1 Kremer LS, L’hermitte- Stead C, Lesimple P, Gilleron M, Filaut S, Jardel C, Haack TB, Strom TM, Meitinger T, Azzouz H, Tebib N, Ogier de Baulny H, Touati G, Prokisch H, Lombès A. Severe respiratory complex III defect prevents liver adaptation to prolonged fasting. J Hepatol 2016 65(2):377-85 (see slides presentation)

    14-2 Tchikviladzé M, Gilleron M, Maisonobe T, Galanaud D, Laforêt P, Durr A, Eymard B, Mochel F, Ogier H, Béhin A, Stojkovic T, Degos B, Gourfinkel-An I, Sedel F, Anheim M, Elbaz A, Viala K, Vidailhet M, Brice A, Jardel C, Lombès A. A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity. J Neurol Neurosurg Psy 2014 86(6):646-54

    14-1Damiano M,Gautier CA, Bulteau AL, Ferrando-Miguel R, Gouarne C, Giraudon Paoli M, Pruss R, Auchère F, L’Hermitte-Stead C, Bouillaud F, Brice A, Corti O, Lombès A. Tissue- and cell-specific mitochondrial defect in Parkin-deficient mice. PLos One 2014;9(6):e99898

    13-3 Auré K, Dubourg O, Jardel C, Clarysse L, Sternberg D, Fournier E, Laforêt P, Streichenberger N, Petiot P, Gervais-Bernard H, Vial C, Bedat-Millet AL, Drouin-Garraud V, Bouillaud F, Vandier C, Fontaine B, Lombès A. Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations. Neurology 2013 81(21):1810-8.

    13-2 Gaignard P, Menezes M, Schiff M Bayot A, Rak M, Ogier de Baulny H, Su CH, Gilleron M, Lombès A, Abida H, Tzagoloff A, Riley L, Cooper ST, Mina K, Davis MR, Allcock RJN, Kresoje N, Laing NG, Thorburn DR, Slama A, Christodoulou J, Rustin P. Mutations in the cytochrome c1 subunit of respiratory 1 chain complex III cause insulin-responsive hyperglycemia. Am J Hum Genet 2013 93(2):384-9.

    13-1 Bertolin G, Ferrando-Miguel R, Jacoupy M, Traver S, Grenier K, Greene AW, Dauphin A, Waharte F, Bayot A, Salamero J, Lombès A, Bulteau AL, Fon EA, Brice A, Corti O. The TOM machinery is a molecular switch in PINK1/PARKIN-dependent mitochondrial clearance. Autophagy 2013 9(11):1801-17.

    12-4 Agier V, Oliviero P, Lainé J, L’Hermitte- Stead C, Girard S, Fillaut S, Jardel C, Bouillaud F, Bulteau AL, Lombès A. Defective mitochondrial fusion, altered respiratory function, and distorted cristae structure in skin fibroblasts with heterozygous OPA1 mutations. BBA-Mol Basis Dis 2012 1822(10):1570-1580.

    12-3 Behin A, Jardel C, Claeys KG, Fagart J, Louha M, Romero NB, Laforêt P, Eymard B, Lombès A. Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum. Neurology 2012 78(9):644-648.

    12-2 Neeve VCM, Samuels DC, Bindoff LA, van den Bosch B, Van Goethem G, Smeets H, Lombès A, Jardel C, Hirano M, DiMauro S, De Vries M, Smeitink J, Smits B, de Coo IFM, Saft C, Klopstock T,  Keiling BC, Czermin B, Abicht A, Lochmüller H, Hudson G, Gorman GG, Turnbull DM, Taylor RW, Holinski Feder H, Chinnery PF, Horvath R. What is influencing the phenotype of the common homozygous polymerase γ mutation p.Ala467Thr?  Brain 2012 135(12) :3614-3626.

    12-1 Weraarpachai W, Sasarman F, Nishimura T, Antonicka H, Auré, K, Rötig A, Lombès A, Shoubridge EA. Mutations in C12orf62, an assembly factor for cytochrome c oxidase, cause a fatal neonatal lactic acidosis. Am Journal Hum Genet 2012 90:142-151.



    Financial supports


    These programs are supported by FRM (Fondation pour la Recherche Médicale), AFM (Association Française contre les Myopathies) and AMMi (Association contre les Maladies Mitochondriales)