title: Rapamycin enhances survival in a Drosophila model of mitochondrial disease.
abstract: Pediatric mitochondrial disorders are a devastating category of diseases caused by deficiencies in mitochondrial function. Leigh Syndrome (LS) is the most common of these diseases with symptoms typically appearing within the first year of birth and progressing rapidly until death, usually by 6-7 years of age. Our lab has recently shown that genetic inhibition of the mechanistic target of rapamycin (TOR) rescues the short lifespan of yeast mutants with defective mitochondrial function, and that pharmacological inhibition of TOR by administration of rapamycin significantly rescues the shortened lifespan, neurological symptoms, and neurodegeneration in a mouse model of LS. However, the mechanism by which TOR inhibition exerts these effects, and the extent to which these effects can extend to other models of mitochondrial deficiency, are unknown. Here, we probe the effects of TOR inhibition in a Drosophila model of complex I deficiency. Treatment with rapamycin robustly suppresses the lifespan defect in this model of LS, without affecting behavioral phenotypes. Interestingly, this increased lifespan in response to TOR inhibition occurs in an autophagy-independent manner. Further, we identify a fat storage defect in the ND2 mutant flies that is rescued by rapamycin, supporting a model that rapamycin exerts its effects on mitochondrial disease in these animals by altering metabolism.
authors.affiliation: University of Washington, Department of Pathology, Seattle, WA, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Wang
authors.affiliation: University of Washington, Department of Pathology, Seattle, WA, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Mouser
authors.affiliation: University of Washington, Department of Pathology, Seattle, WA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Pitt
authors.affiliation: University of Washington, Department of Pathology, Seattle, WA, USA.|University of Washington, Department of Biology, Seattle, WA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Promislow
authors.affiliation: University of Washington, Department of Pathology, Seattle, WA, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000187:drug effects; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008136:Longevity / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D029721:Drosophila Proteins; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D042967:Electron Transport Complex I; D020123:Sirolimus
keywords: Drosophila; complex I; leigh syndrome; mitochondria; rapamycin