A team of CNRS 6214/INSERM 1083

Mitochondrial dynamics & bioenergetics

Main achievements over the past four years

The organization of a fibroblast biobank. We set up a biobank of fibroblasts to serve as models for investigating bioenergetics in the context of diseases due to defective mitochondrial dynamics. Skin fibroblasts were obtained from patients carrying carrying OPA1, MFN2, GDAP1 and mtDNA mutations, as well as from controls. These cells allowed the characterization of the molecular and biochemical processes involved in the mitochondrial dynamics of the diseases. The fibroblasts showed respiratory chain defects similar to those observed in classical mtDNA diseases. OPA1 mutations were associated with altered OXPHOS coupling efficiency accompanied by impaired ATP production, and complex IV deficiency accompanied by a compensatory increase in ATP synthase activity. MFN2 mutations were associated with altered OXPHOS coupling efficiency but without deficiency of ATP synthesis. GDAP1 mutations were associated with complex I deficiency. Several metabolic investigations are currently under way, e.g. measurement of enzyme activities involved in energy metabolism, together with metabolomic and transcriptomic studies.

The visualization of mitochondrial dynamics. We described the altered mitochondrial network structure in fibroblasts carrying the OPA1, MFN2, and GDAP1 mutations. Most of the fibroblasts with OPA1 mutations showed mitochondrial fragmentation whereas fibroblasts with MFN2 and mtDNA mutations showed highly dense, interconnected mitochondrial networks. Fibroblasts with GDAP1 mutations showed lesser fragmentation of the mitochondrial network with greater mitochondrial diameters in electron microscopy compared to controls.

The investigation of bioenergetics in mouse models of ADOA/OPA1 and CMT2A/MFN2. In collaboration with Guy Lenaers, we studied the bioenergetic metabolism of a new mouse model (OPA1+/-) reproducing the ADOA phenotype. We found an OXPHOS deficiency in the retina of these mice. The OPA1+/- mouse offers an interesting model for testing pharmacological therapeutic approaches. In collaboration with Jean-Claude Martinou, we found complex II and V deficiencies in the brain of a mouse model with an MFN2 mutation reproducing the CMT2A phenotype. In addition, we found that these deficiencies of the respiratory chain were related to the constitutional activation of the mKATP channel, a heteromultimeric complex of the mitochondrial membrane that includes complexes II and V.

References

  • Loiseau D, Chevrollier A, Verny C, Guillet V, Gueguen N, Pou de Crescenzo MA, Ferré M, Malinge MC, Guichet A, Nicolas G, Amati-Bonneau P, Malthièry Y, Bonneau D, Reynier P. Mitochondrial Coupling Defect in Charcot-Marie-Tooth Type 2A Disease. Ann Neurol 2007;61:315-23.
  • Chevrollier A, Guillet V, Loiseau D, Gueguen N, Pou de Crescenzo MA, Verny C, Ferre M, Dollfus H, Odent S, Milea D, Goizet C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P. Hereditary optic neuropathies share a common mitochondrial coupling defect. Ann Neurol 2008;63:794-8.
  • Amati-Bonneau P, Milea D, Bonneau D, Chevrollier A, Ferré M, Guillet V, Gueguen N, Loiseau D, Pou de Crescenzo MA, Verny C, Procaccio V, Lenaers G, Reynier P. OPA1-associated disorders: Phenotypes and pathophysiology. Int J Biochem Cell Biol 2009;41:1855-65. Review.
  • Lenaers G, Amati-Bonneau P, Delettre C, Chevrollier A, Verny C, Miléa D, Procaccio V, Bonneau D, Hamel C, Reynier P. From yeast to neurodegenerative diseases: Ten years of exploration of mitochondrial dynamic disorders. Med Sci (Paris) 2010, In press.

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 Irvine (S Cramer)