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

作者：Rahman Motiur; Nirala Niraj K; Singh Alka; Zhu Lihua Julie; Taguchi Kaori; Bamba Takeshi; Fukusaki Eiichiro; Shaw Leslie M; Lambright David G; Acharya Jairaj K; Acharya Usha R^*

来源：The Journal of Cell Biology, 2014, 206(2): 289-305.

DOI：10.1083/jcb.201404118

Adenosine 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 deacetylotion, increased complex V activity, whereas substitution with Gin, 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 mitochondria' 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.

• 出版日期2014-7-21