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Barriocanal-Casado 2015 Abstract MiP2015

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Targeting nutrient signaling pathways for the treatment of mitochondrial diseases.


Barriocanal-Casado E, Luna-Sanchez M, Hidalgo-Gutierrez A, Cueto-Urena C, Lopez LC (2015)

Event: MiP2015

Mitochondrial diseases are disorders with heterogeneous manifestations, with central nervous system (CNS) and muscle being the most severely affected. Despite the advances in the understanding of he pathophysiology of mitochondrial diseases, there are only few cases of effective treatments. To test potential therapies, we recently generated a mouse model of Coenzyme Q (CoQ) deficiency (Coq9R239X) that presents a dysfunctional COQ9 protein, which causes widespread CoQ deficiency and mitochondrial encephalomyopaty [1]. Recent studies have shown that inhibition of mechanistic target of rapamycin complex 1(mTORC1), a protein kinase involved in the control of many anabolic and catabolic process in the cell, by rapamycin administration produces therapeutic benefits in some animal and cellular models of mitochondrial diseases [2,3]. However, it is not known whether mTORC1 inhibition would be useful in all cases of mitochondrial diseases and the mechanism by which rapamycin delays progression of the disease in the mouse models is not clear. To answer these questions, we have evaluated the effects of rapamycin treatment in the Coq9R239X mouse model. Mice were treated with oral rapamycin in their chow at a concentration of 14 mg/kg food, which corresponds to a dose of 2.24 mg of rapamycin per kg b.w./day (equivalent to a dose of 0.2 mg per kg body weight/day in humans when normalized by body surface area). The treatment started at 1 month of age and we analyzed the animals at 3 months of age. We evaluated the therapeutic effects by immunohistochemistry in different brain sections to determine if rapamycin treatment ameliorates the vacuolization and astrogliosis in Coq9R239X mice. Moreover, we carried out a metabolomic analysis and measured CoQ levels and mitochondrial complexes activities. We also evaluated some autophagy markers by western blot.

Our results show that rapamycin produces neurological improvement in Coq9R239X mice. These benefits may be due to changes in the metabolic profile of treated Coq9R239X mice, while the biosynthetic pathway of CoQ is not affected by rapamycin treatment. Therefore, rapamycin seems to have therapeutics effects in mitochondrial encephalopathy associated to CoQ deficiency. These therapeutic benefits are the result of the modulation of mTORC1 downstream pathways.

Labels: MiParea: Respiration, mtDNA;mt-genetics, Pharmacology;toxicology 

Stress:Mitochondrial disease  Organism: Mouse 

Event: A3, Oral  MiP2015, Rapamycin 


1-Dept Fisiología, Facultad de Medicina, Univ Granada, Spain; 2-Centro Investigación Biomédica, Inst Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain. -

References and acknowledgements

  1. Luna-Sanchez M, Diaz-Casado E, Barca E, Tejada MA, Montilla-Garcia A, Cobos EJ, Escames G, Acuña-Castroviejo D, Quinzii CM, López LC (2015) The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene. EMBO Mol Med 7:670-87.
  2. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, Palmiter RD, Rabinovitch PS, Morgan PG, Sedensky MM, Kaeberlein M (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342:1524-8.
  3. Peng M, Ostrovsky J, Kwon YJ, Polyak E, Licata J, Tsukikawa M, Marty E, Thomas J, Felix CA, Xiao R, Zhang Z, Gasser DL, Argon Y, Falk MJ (2015) Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease. Hum Mol Genet [in press].