PuSH - Publication Server of Helmholtz Zentrum München: <em>Drosophila</em> miR-277 controls branched-chain amino acid catabolism and affects lifespan.

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Esslinger, S.M.* ; Schwalb, B.* ; Helfer, S.* ; Michalik, K.M.* ; Witte, H. ; Maier, K.C.* ; Martin, D.* ; Michalke, B. ; Tresch, A.* ; Cramer, P.* ; Forstemann, K.*

Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan.

RNA Biol. 10, 1042-1056 (2013)

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Open Access Green as soon as Postprint is submitted to ZB.

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords ageing; diabetes; longevity; maple syrup urine disease (MSUD); metabolic syndrome; miRNA; miRNA target validation; Microrna Target Predictions ; Skeletal-muscle ; Mitochondrial Biogenesis ; Dehydrogenase Complex ; Insulin-resistance ; Signaling Pathway ; Protein-synthesis ; Mammalian-cells ; Rna-synthesis ; Melanogaster

ISSN (print) / ISBN 1547-6286

e-ISSN 1555-8584

Journal RNA Biology

Quellenangaben Volume: 10, Issue: 6, Pages: 1042-1056

Publisher Landes Bioscience

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Analytical BioGeoChemistry (BGC)