title: SIRT5 is under the control of PGC-1α and AMPK and is involved in regulation of mitochondrial energy metabolism.
abstract: The sirtuins (SIRTs; SIRT1-7) are a family of NAD(+)-dependent enzymes that dynamically regulate cellular physiology. Apart from SIRT1, the functions and regulatory mechanisms of the SIRTs are poorly defined. We explored regulation of the SIRT family by 2 energy metabolism-controlling factors: peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase (AMPK). Overexpression of PGC-1α in mouse primary hepatocytes increased SIRT5 mRNA expression 4-fold and also the protein in a peroxisome proliferator-activated receptor α (PPARα)- and estrogen-related receptor α (ERRα)-dependent manner. Furthermore, food withdrawal increased SIRT5 mRNA 1.3-fold in rat liver. Overexpression of AMPK in mouse hepatocytes increased expression of SIRT1, SIRT2, SIRT3, and SIRT6 <2-fold. In contrast, SIRT5 mRNA was down-regulated by 58%. The antidiabetes drug metformin (1 mM), an established AMPK activator, reduced the mouse SIRT5 protein level by 44% in cultured hepatocytes and by 31% in liver in vivo (300 mg/kg, 7 d). Metformin also induced hypersuccinylation of mitochondrial proteins. Moreover, SIRT5 overexpression increased ATP synthesis and oxygen consumption in HepG2 cells, but did not affect mitochondrial biogenesis. In summary, our results identified SIRT5 as a novel factor that controls mitochondrial function. Moreover, SIRT5 levels are regulated by PGC-1α and AMPK, which have opposite effects on its expression.-Buler, M., Aatsinki, S.-M., Izzi, V., Uusimaa, J., Hakkola, J. SIRT5 is under the control of PGC-1α and AMPK and is involved in regulation of mitochondrial energy metabolism.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, Medical Research Center Oulu and.
authors.forename: Marcin
authors.initials: M
authors.lastname: Buler
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, Medical Research Center Oulu and.
authors.forename: Sanna-Mari
authors.initials: SM
authors.lastname: Aatsinki
authors.affiliation: Center for Cell-Matrix Research and Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, and.
authors.forename: Valerio
authors.initials: V
authors.lastname: Izzi
authors.affiliation: Medical Research Center Oulu and Institute of Clinical Medicine and Pediatrics, Clinical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Biomedicine, Medical Research Center Oulu and jukka.hakkola@oulu.fi.
authors.forename: Jukka
authors.initials: J
authors.lastname: Hakkola
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D055372:AMP-Activated Protein Kinases; D047493:PPAR alpha; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D037761:Sirtuins; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor
keywords: ATP; ERRα; PPARα; metformin