A team of CNRS 6015/INSERM 1083

Mitochondrial translational research & diseases

Main achievements over the past four years

The determination of phenotype-genotype correlations and the definition of new clinical entities. We have shown that the clinical spectrum of ADOA was larger than previously thought. Specific OPA1 mutations are responsible for several distinct clinical presentations, such as ADOA with deafness (ADOAD), and severe multisystemic syndromes, the so-called “ADOA plus” disorders, which involve neurological and neuromuscular symptoms similar to those due to defective OxPhos activity associated with mtDNA mutations.

The representation of the spectrum of OPA1 mutations. Our group has discovered more than half of all the OPA1 mutations reported so far. We have posted the eOPA1, a locus-specific database, on the internet to register OPA1 sequence variations (http://lbbma.univ-angers.fr/eOPA1/). All the OPA1 mutations and non-pathogenic sequence variants are included in this database by the curator as soon as these are published or directly submitted by external investigators. The database currently contains 213 pathogenic OPA1 mutations (updated July 2010). These mutations, which are often family-specific, are spread all through the OPA1 protein; however, the GTPase domain, the dynamin central region and the C-terminal domain are more frequently affected. These mutations are mostly family-specific, but one mutation in exon 27 (c.2708_2711del), found in about 17% of the cases, represents a mutational hot spot.

The characterization of diseases associated with OPA1 and mtDNA mutations. The most striking finding was that most of OPA1 patients harbored multiple mtDNA deletions in their skeletal muscles, suggesting that OPA1 plays a key role in mtDNA maintenance. A recent collaborative study of 104 patients from 45 unrelated families summed up the new clinical forms described over the past 10 years. Nearly 20% of OPA1 patients suffer from extraocular impairment associated with optic atrophy, these clinical forms being described as AOAD+. The commonest extraocular symptom is a bilateral sensorineural deafness appearing first in adolescence and then developing progressively. Syndromes with ataxia, myopathy, peripheral neuropathy and chronic progressive external ophthalmoplegia are less common. It should be noted that this wide range of symptoms may be superposed on that observed in diseases classically associated with defective functioning of the mitochondrial respiratory chain.

Alongside the main project focusing on mitochondrial dynamics outlined above, our team has engaged in various translational research activities related to mitochondria and energetic metabolism. These include studies of various mitochondrial, metabolic and neurogenetic diseases as well as of mitochondrial involvement in reproductive biology and infertility.


  • Hudson G, Amati-Bonneau P, Blakely EL, Stewart JD, He L, Schaefer AM,Griffiths PG, Ahlqvist K, Suomalainen S, Reynier P, McFarland R, Turnbull DM, Chinnery PF, Taylor RW. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain. 2008;131:329-37.
  • Amati-Bonneau P, Valentino ML, Reynier P, Gallardo E, Bornstein B, Boissière A, Campos Y, Rivera H, González de la Aleja J, Carroccia R, Iommarini L, Labauge P, Figarella-Branger D, Marcorelles P, Furby A, Beauvais K, Letournel F, Liguori R, La Morgia C, Montagna P, Liguori M, Zanna C, Rugolo M, Cossarizza A, Wissinger B, Verny C, Schwarzenbacher R, Ángel Martín M, Arenas J, Ayuso C, Garesse R, Lenaers G, Bonneau D, Carelli V. OPA1 mutations induce mitochondrial DNA instability and optic atrophy “plus” phenotypes. Brain 2008;131:338-51.
  • Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M , Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques WJr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain 2010;133:771-86.
  • Ferré M, Bonneau D, Chevrollier A, Dollfus H, Milea D, Ayuso C, Defoort S, Vignal C, Zanlonghi X, Charlin JF, Kaplan J, Odent S, Hamel C, Procaccio V, Reynier P, Amati-Bonneau P. Molecular screening of 980 cases of suspected of hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Hum Mutat 2009;30:E692-705.

Reference activities of the Mitochondrial Research Team

  • ERA-NET E-Rare 2010-2013, “European Research project on Mendelian Inherited Optic Neuropathies” coordinated by Dominique Bonneau (in collaboration with Martinuzzi Adrea, Conegliano, Italy; Valerio Carelli, Bologna, Italy; Bernt Wissinger, Tubingen, Germany; Guy Lenaers, Montpellier, France)
  • National reference center on neurogenetic disorders (Coordinators: Dominique Bonneau, Christophe Verny)
  • National reference center on Mitochondrial Diseases coordinated by Arnold Munnich (Necker, Bicetre, Bordeaux, Nice-Marseille, Angers)
  • Coordination of the French Mitochondrial Disease network (Pascal Reynier).
  • Participation to the head group coordinating the « MeetOchondrie » network (Pascal Reynier).
  • The Department of Biochemistry and Molecular Biology of Angers University Hospital (Pascal Reynier) is expert in the diagnosis of mitochondrial diseases.

Main collaborations of the Mitochondrial Research Team

  • National reference center for Neurosensorial Genetic Disorders of Montpellier University Hospital (C Hamel)
  • National reference center for Neurosensorial Genetic Disorders of Strasbourg University Hospital (H Dollfus)
  • Medical Genetics (S Odent) in Rennes University hospital
  • Inserm U583, Montpellier (G Lenaers, C Hamel)
  • CNRS UMR5088, Toulouse (P Belenguer)
  • Inserm U688, Bordeaux (T Letellier, R Rossignol)
  • V Carelli, University of Bologna
  • P Chinnery, University of Newcastle
  • JC Martinou, University of Geneva.
  • University of Philadelphia (DC Wallace)
  • University of Irvine (S Cramer)