title: Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan.
abstract: Development, growth and adult survival are coordinated with available metabolic resources, ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21-23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is downregulated during adult life. Molecular analysis revealed that this miRNA controls branched-chain amino acid (BCAA) catabolism and as a result it can modulate the activity of the TOR kinase, a central growth regulator, in cultured cells. Metabolite analysis in cultured cells as well as flies suggests that the mechanistic basis may be an accumulation of branched-chain α-keto-acids (BCKA), rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g., translational fidelity. Constitutive miR-277 expression shortens lifespan and is synthetically lethal with reduced insulin signaling, indicating that metabolic control underlies this phenotype. Transgenic inhibition with a miRNA sponge construct also shortens lifespan, in particular on protein-rich food. Thus, optimal metabolic adaptation appears to require tuning of cellular BCAA catabolism by miR-277.
authors.affiliation: Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, München, Germany.
authors.forename: Stephanie Maria
authors.initials: SM
authors.lastname: Esslinger
authors.forename: Björn
authors.initials: B
authors.lastname: Schwalb
authors.forename: Stephanie
authors.initials: S
authors.lastname: Helfer
authors.forename: Katharina Maria
authors.initials: KM
authors.lastname: Michalik
authors.forename: Heidi
authors.initials: H
authors.lastname: Witte
authors.forename: Kerstin C
authors.initials: KC
authors.lastname: Maier
authors.forename: Dietmar
authors.initials: D
authors.lastname: Martin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Michalke
authors.forename: Achim
authors.initials: A
authors.lastname: Tresch
authors.forename: Patrick
authors.initials: P
authors.lastname: Cramer
authors.forename: Klaus
authors.initials: K
authors.lastname: Förstemann
mesh_terms: D000375:Aging; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D007328:Insulin / Q000378:metabolism; D008136:Longevity; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000597:Amino Acids, Branched-Chain; D007328:Insulin; D035683:MicroRNAs; D058570:TOR Serine-Threonine Kinases
keywords: ageing; diabetes; longevity; maple syrup urine disease (MSUD); metabolic syndrome; miRNA; miRNA target validation