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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)
Verlagsversion Volltext DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift RNA Biology
Quellenangaben Band: 10, Heft: 6, Seiten: 1042-1056 Artikelnummer: , Supplement: ,
Verlag Landes Bioscience
Begutachtungsstatus Peer reviewed