Sirt4 is a mitochondrial regulator of metabolism and lifespan in Drosophila melanogaster

Sirtuins are an evolutionarily conserved family of NAD⁺-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies ha...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 7; pp. 1564 - 1569
Main Authors Wood, Jason G., Schwer, Bjoern, Wickremesinghe, Priyan C., Hartnett, Davis A., Burhenn, Lucas, Garcia, Meyrolin, Li, Michael, Verdin, Eric, Helfand, Stephen L.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 13.02.2018
Subjects
Amino acids
Animals
Animals, Genetically Modified - genetics
Animals, Genetically Modified - growth & development
Animals, Genetically Modified - metabolism
Biological Sciences
Catabolism
Chain branching
Control stability
Drosophila melanogaster
Drosophila melanogaster - genetics
Drosophila melanogaster - growth & development
Drosophila melanogaster - metabolism
Energy balance
Energy reserves
Fasting
Fasting - physiology
Fat body
Fatty acids
Female
Fertility
Fertility - physiology
Flies
Genotype & phenotype
Glycogen
Glycolysis
Homeostasis
Insects
Internal energy
Life span
Lipid metabolism
Lipids
Longevity
Male
Metabolism
Metabolomics
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
NAD
Sirtuins
Sirtuins - genetics
Sirtuins - metabolism
Trehalose
metabolism
aging
mitochondria
sirtuins
Sirt4
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Summary:Sirtuins are an evolutionarily conserved family of NAD⁺-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies have a short lifespan, with increased sensitivity to starvation and decreased fertility and activity. In contrast, flies overexpressing Sirt4 either ubiquitously or specifically in the fat body are long-lived. Despite rapid starvation, Sirt4 knockout flies paradoxically maintain elevated levels of energy reserves, including lipids, glycogen, and trehalose, while fasting, suggesting an inability to properly catabolize stored energy. Metabolomic analysis indicates several specific pathways are affected in Sirt4 knockout flies, including glycolysis, branched-chain amino acid metabolism, and impaired catabolism of fatty acids with chain length C18 or greater. Together, these phenotypes point to a role for Sirt4 in mediating the organismal response to fasting, and ensuring metabolic homeostasis and longevity.
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1Present addresses: Department of Neurological Surgery and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94158.
Author contributions: J.G.W., B.S., E.V., and S.L.H. designed research; J.G.W., B.S., P.C.W., D.A.H., L.B., M.G., and M.L. performed research; J.G.W. and B.S. analyzed data; and J.G.W., B.S., and S.L.H. wrote the paper.
Edited by Nancy M. Bonini, University of Pennsylvania, Philadelphia, PA, and approved December 29, 2017 (received for review November 28, 2017)
2Present address: Buck Institute for Research on Aging, Novato, CA 94945.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1720673115