Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase beta and regulates complex V activity
Nirala, Niraj K.
Zhu, Lihua Julie
Shaw, Leslie M.
Lambright, David G.
Acharya, Jairaj K.
Acharya, Usha R.
UMass Chan AffiliationsDepartment of Cancer Biology
Program in Molecular Medicine
Program in Gene Function and Expression
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AbstractAdenosine triphosphate (ATP) synthase beta, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase beta 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 beta 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 beta, 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.
SourceRahman M, Nirala NK, Singh A, Zhu LJ, Taguchi K, Bamba T, Fukusaki E, Shaw LM, Lambright DG, Acharya JK, Acharya UR. Drosophila Sirt2/mammalian SIRT3 deacetylates ATP synthase β and regulates complex V activity. J Cell Biol. 2014 Jul 21;206(2):289-305. doi: 10.1083/jcb.201404118. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/44040
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