Authors: Esslinger SM; Schwalb B; Helfer S; Michalik KM; Witte H; Maier KC; Martin D; Michalke B; Tresch A; Cramer P; Förstemann K
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 alpha-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.
Journal: RNA biology
Date: May 15, 2013
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Esslinger SM, Schwalb B, Helfer S, Michalik KM, Witte H, Maier KC, Martin D, Michalke B, Tresch A, Cramer P, Förstemann K (2013) Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan. RNA biology.