title: Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.
abstract: Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA; Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, 3086, Australia.
authors.forename: Rommel A
authors.initials: RA
authors.lastname: Mathias
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Greco
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Oberstein
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Hanna G
authors.initials: HG
authors.lastname: Budayeva
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Rumela
authors.initials: R
authors.lastname: Chakrabarti
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Rowland
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Shenk
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA. Electronic address: icristea@princeton.edu.
authors.forename: Ileana M
authors.initials: IM
authors.lastname: Cristea
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D011768:Pyruvate Dehydrogenase Complex; D005973:Glutamine; D008063:Thioctic Acid; C013091:lipoamide; D000581:Amidohydrolases; C525357:SIRT4 protein, human; C514813:SIRT4 protein, mouse; D037761:Sirtuins; C023940:lipoamidase