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MitoVasc : physiopathologie cardiovasculaire et mitochondriale


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    Mitochondrial genetics ans therapeutics

    Mitochondrial genetics ans therapeutics

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      Separated by coma
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    Vincent Procaccio

    Photo Vincent Procaccio

     

     

     

     

     

     

     

    Team members : 

    Pascal Reynier, M.D., Ph.D.

    Dominique Bonneau, M.D., Ph.D.

    Vincent Procaccio, M.D., Ph.D.

    Pascale May-Panloup, M.D., Ph.D.

    Delphine Prunier Mirebeau, M.D., Ph.D.

    Julien Cassereau, M.D., Ph.D.

    Arnaud Chevrollier, Ph.D.

    Marc Ferré, Ph.D.

    Patrizia Amati-Bonneau, M.D.

    Valérie Desquiret-Dumas, Engineer Ph.D.

    Naig Guéguen, Engineer Ph.D

    Sophie Belal, Engineer 

    Jennifer Alban, Technician

    Stéphanie Chupin, Technician

    Aurore Inisan, Technician

    Céline Bris, M.D., Ph.D. Student

    Julien Chao de la Barca, M.D., Ph.D. Student

    Charlotte Veyrat Durebex, M.D., Ph.D. Student

    Estelle Colin, M.D., Ph.D. Student

    Stéphanie Leruez, Ph.D. Student

    Guillaume Geoffroy, Ph.D. Student 

    Selma Kane, Ph.D. Student

     

    Main achievements over the past four years:

    Mutations of mitochondrial genome (mtDNA) are also responsible for respiratory chain defects in numerous patients. The clinical manifestations of mtDNA-related diseases may be very variable even within the same family. Indeed, normal and mutated mtDNAs may coexist within cells, a condition known as heteroplasmy.  We have developed a new strategy for the rapid identification of heteroplasmic mtDNA mutations. This method, which is based on the use of a new mismatch-specific DNA endonuclease, named « Surveyor Nuclease », enables the systematic screening of the entire mitochondrial genome rapidly and can detect different mutants present at as low as 3% hétéroplasmy. We have recently created heteroplasmic neuronal cybrid cells harboring known deleterious mtDNA mutations and determined the effects of mitochondrial defects on their growth and differentiation capacity.
    Several studies have revealed that specific mitochondrial DNA (mtDNA) lineages are associated with reduced neurodegenerative disease and increased longevity.  Our genetic aim is to analyze the role of mitochondrial genetic variations in recovery from stroke and in longevity. For instance, a better understanding of the contribution of genetic factors to stroke recovery, and its inter-individual variability, could be useful to improve therapeutics. Mitochondrial impairment during stroke recovery can result in a cellular energy deficiency and also increased ROS production.  Clinical studies, as well as cellular and animal stroke models, suggest that recovery phase neuronal plasticity is highly sensitive to energetic perturbation, oxidative stress, and resultant programmed cell death. 
    Little is known regarding the mitochondrial contribution to endothelial dysfunction, a key paradigm for vascular disease and age-associated disorders such as stroke. While women aged 30 to 50 have about five times lower risk of stroke and cardiovascular disease than men, this difference disappears when women reach menopause, suggesting that estrogen plays a major role.  Using ovarietomized female rats, we demonstrated that in vivo estrogen replacement at physiological doses led to increased levels of key mitochondrial proteins in cerebral blood vessels, including cytochrome c, mitochondrial transcription factors and antioxidant enzymes. Furthermore, estrogen decreases mitochondrial ROS production. This study demonstrates that estrogen and other related molecules increases mitochondrial efficiency while decreasing ROS production providing insight into the role of mitochondria in preventing cerebrovascular dysfunction, and increasing our knowledge of how endogenous estrogen and estrogen-related therapies impact vascular function.

    Spotlight References

    • Ruiz-Pesini E, Mishmar D, Brandon M., Procaccio V, Wallace DC. Distinguishing the effect of purifying and adaptive selection on regional variation in human mtDNA. Science (2004) 303:223-6.
    • Razmara A, Sunday L, Stirone C., Krause D.N., Duckles S.P, Procaccio V.  Mitochondrial effects are mediated by ER alpha in brain endothelial cells. Journal of Pharmacology and Experimental Therapeutics (2008) 325: 782-790.
    • Bannwarth S., Procaccio V., Rouzier C., Fragaki K., Poole J., Vialettes B., Chabrol B., Desnuelle C., Pouget J., Azulay J.P., Attarian S., Pellissier J.F., Gargus J., Abdenur J., Mozaffar T., Calvas P., Labauge P., Raccah D., Pages M., Wallace D.C., Lambert J.C., Paquis-Flucklinger V.. Rapid identification of mitochondrial DNA (mtDNA) mutations in neuromuscular disorders by using Surveyor strategy. Mitochondrion (2008) 8: 136-145.
    • Wallace D.C., Fan W., Procaccio V. Mitochondrial Energetics and Therapeutics. Annual Review of Pathology: Mechanisms of Disease (2010) 5:297-348.

     

     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)