DrosophilamiR-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.

Genome-Wide Analysis of Differentially Expressed microRNA in Bombyx mori Infected with Nucleopolyhedrosis Virus

“…Drosophila miR-277 is down regulated during the adult life, and controls branched-chain amino acid catabolism. Constitutive miR-277 expression shortens lifespan [36] and plays a role as a metabolic switch controlling amino acid catabolism by targeting the metabolic pathway enzymes [37]. MiR-277 has been also reported to be associated with freeze tolerance in insects [38] and to modulate rCGG repeat-mediated neurodegeneration [39].…”

Identification of miR‐305, a microRNA that promotes aging, and its target mRNAs in Drosophila

“…Lastly, miR-200 is widely conserved in eukaryotic genomes, from C. elegans to humans, and can stimulate the proliferation of tumor cells (Korpal et al, 2011;Michael, O'Connor, van Holst Pellekaan, Young, & James, 2003). In addition, previous studies have suggested that another three Drosophila miRNAs, are also implicated in aging-related processes (Esslinger et al, 2013;Hilgers, Bushati, & Cohen, 2010;Xu, Vernooy, Guo, & Hay, 2003). Thus, we included these three miRNAs in our analyses, to further investigate whether the over-expression of these miR-NAs at the adult stage can influence lifespan in flies.…”

Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila

“…Third, all major epigenetic mechanisms (e.g., DNA methylation, histone modifications and non-coding RNA) are present in this fly model system [26], although DNA methylation in flies appears to be different from other eukaryotic organisms and present only at a very low level in adults [27, 28]. Clear evidence has demonstrated that histone modifications [13, 29–32] and at least two microRNAs [33, 34] participate in the regulation of longevity. Finally, recent demonstration of nutritional programming of metabolism and longevity up to the F2 generation [11, 12] has revealed the post-eclosion adult stage to be suitable for assaying the epigenetic mechanisms underlying transgenerational programming of longevity in Drosophila .…”