mitoFIBRATE:

Effect of fibrates on respiratory chain enzyme activity in mitochondrial disorders

State of the art

Mitochondrial disorders (MD) are congenital disorders of energy metabolism - in particular defects of the respiratory chain complexes IV and the pyruvate dehydrogenase complex - with an estimated incidence of 1:8500. The clinical spectrum ranges from severe, lethal neonatal forms to mild gradients in adulthood. They are multi-system diseases, where especially organs with high energy requirements are affected. Prognosis is usually poor. In contrast to progress in understanding the molecular basis of MDs, we are still extremely limited in treating these conditions. The treatment is restricted to symptomatic treatment and administration of vitamins and cofactors.

Aims of the project

We want to analyse drug effects in cell lines from mitochondrial patients. We aim to investigate the effect of riboflavin and coenzyme Q10, two cofactors which are already used in mitochondrial therapy showing positive results in a proportion of patients. We plan to analyse the effect of bezafibrate, a substance which activates mitochondria via PPARs. We will analyse if it is possible to predict the therapeutical effect by cell culture experiments before treating patients. In addition, a clinical study for the treatment of patients from the mitoNET with bezafibrate is in preparation.

Project management and contact addresses

Peter Freisinger, PD Dr. med.
Klinikum Am Steinenberg
Klinik für Kinder-und Jugendmedizin, Perinatal- u. Stoffwechselzentrum
Steinenbergstrasse 31, 72764 Reutlingen

Tel: +49 7121 200 3412
Fax: +49 7121 200 3571
E-mail: freisinger.p@kreiskliniken-reutlingen.de


Holger Prokisch, Dr.
Institut für Humangenetik
Technischen Universität München
Klinikum Rechts der Isar
Trogerstr. 32, 81675 München, Germany

Tel: +49 89 3187 2890
Fax: +49 89 3187 3297
E-mail: prokisch@helmholtz-muenchen.de

Publications:

  1. Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H. (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 42:1131-4.
  2. Gerards M, van den Bosch BJ, Danhauser K, Serre V, van Weeghel M, Wanders RJ, Nicolaes GA, Sluiter W, Schoonderwoerd K, Scholte HR, Prokisch H, Rötig A, de Coo IF, Smeets HJ. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain. 134:210-9.
  3. Herzer M, Koch J, Prokisch H, Rodenburg R, Rauscher C, Radauer W, Forstner R, Pilz P, Rolinski B, Freisinger P, Mayr JA, Sperl W. (2010) Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect. Neuropediatrics. 41:30-4.
  4. O'Toole JF, Liu Y, Davis EE, Westlake CJ, Attanasio M, Otto EA, Seelow D, Nurnberg G, Becker C, Nuutinen M, Kärppä M, Ignatius J, Uusimaa J, Pakanen S, Jaakkola E, van den Heuvel LP, Fehrenbach H, Wiggins R, Goyal M, Zhou W, Wolf MT, Wise E, Helou J, Allen SJ, Murga-Zamalloa CA, Ashraf S, Chaki M, Heeringa S, Chernin G, Hoskins BE, Chaib H, Gleeson J, Kusakabe T, Suzuki T, Isaac RE, Quarmby LM, Tennant B, Fujioka H, Tuominen H, Hassinen I, Lohi H, van Houten JL, Rotig A, Sayer JA, Rolinski B, Freisinger P, Madhavan SM, Herzer M, Madignier F, Prokisch H, Nurnberg P, Jackson PK, Khanna H, Katsanis N, Hildebrandt F. (2010) Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest. 120:791-802.
  5. Pham TT, Giesert F, Röthig A, Floss T, Kallnik M, Weindl K, Hölter SM, Ahting U, Prokisch H, Becker L, Klopstock T, Hrabé de Angelis M, Beyer K, Görner K, Kahle PJ, Vogt Weisenhorn DM, Wurst W. (2010) DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments. Genes Brain Behav. 9:305-17
  6. Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmüller H, D'Adamo P, Gasparini P, Strom TM, Prokisch H, Invernizzi F, Ferrero I, Zeviani M. (2009) SDHAF1,encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet. 4:654-6.
  7. Elstner M, Andreoli C, Klopstock T, Meitinger T, Prokisch H. (2009) The mitochondrial proteome database: MitoP2. Methods Enzymol. 457:3-20.
  8. Ahting U, Floss T, Uez N, Schneider-Lohmar I, Becker L, Kling E, Iuso A, Bender A, de Angelis MH, Gailus-Durner V, Fuchs H, Meitinger T, Wurst W, Prokisch H, Klopstock T. (2009) Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import. Biochim
    Biophys Acta. 1787:371-6.