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J Cell Biol. 2014 Jul 21;206(2):289-305. doi: 10.1083/jcb.201404118. Epub 2014 Jul 14.

Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity.

Author information

1
Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
2
Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
3
Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan.
4
Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.
5
Laboratory of Cell and Developmental Signaling, National Cancer Institute, Frederick, MD 21702.
6
Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605Program in Gene Function and Expression, Program in Molecular Medicine, Program in Bioinformatics and Integrative Biology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605 usha.acharya@umassmed.edu.

Abstract

Adenosine triphosphate (ATP) synthase β, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase β is deacetylated by a human nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue, dSirt2. dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase β and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase β, mimicking deacetylation, increased complex V activity, whereas substitution with Gln, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from wild-type and dsirt2 mitochondria identified the Drosophila mitochondrial acetylome and revealed dSirt2 as an important regulator of mitochondrial energy metabolism. Additionally, we unravel a ceramide-NAD(+)-sirtuin axis wherein increased ceramide, a sphingolipid known to induce stress responses, resulted in depletion of NAD(+) and consequent decrease in sirtuin activity. These results provide insight into sirtuin-mediated regulation of complex V and reveal a novel link between ceramide and Drosophila acetylome.

PMID:
25023514
PMCID:
PMC4107778
DOI:
10.1083/jcb.201404118
[Indexed for MEDLINE]
Free PMC Article

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