title: Overexpression of mitochondrial sirtuins alters glycolysis and mitochondrial function in HEK293 cells.
abstract: SIRT3, SIRT4, and SIRT5 are mitochondrial deacylases that impact multiple facets of energy metabolism and mitochondrial function. SIRT3 activates several mitochondrial enzymes, SIRT4 represses its targets, and SIRT5 has been shown to both activate and repress mitochondrial enzymes. To gain insight into the relative effects of the mitochondrial sirtuins in governing mitochondrial energy metabolism, SIRT3, SIRT4, and SIRT5 overexpressing HEK293 cells were directly compared. When grown under standard cell culture conditions (25 mM glucose) all three sirtuins induced increases in mitochondrial respiration, glycolysis, and glucose oxidation, but with no change in growth rate or in steady-state ATP concentration. Increased proton leak, as evidenced by oxygen consumption in the presence of oligomycin, appeared to explain much of the increase in basal oxygen utilization. Growth in 5 mM glucose normalized the elevations in basal oxygen consumption, proton leak, and glycolysis in all sirtuin over-expressing cells. While the above effects were common to all three mitochondrial sirtuins, some differences between the SIRT3, SIRT4, and SIRT5 expressing cells were noted. Only SIRT3 overexpression affected fatty acid metabolism, and only SIRT4 overexpression altered superoxide levels and mitochondrial membrane potential. We conclude that all three mitochondrial sirtuins can promote increased mitochondrial respiration and cellular metabolism. SIRT3, SIRT4, and SIRT5 appear to respond to excess glucose by inducing a coordinated increase of glycolysis and respiration, with the excess energy dissipated via proton leak.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Michelle Barbi
authors.initials: MB
authors.lastname: de Moura
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Radha
authors.initials: R
authors.lastname: Uppala
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yuxun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh of The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Goetzman
mesh_terms: D019069:Cell Respiration; D005947:Glucose / Q000494:pharmacology; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C466093:SIRT3 protein, human; C525357:SIRT4 protein, human; C508544:SIRT5 protein, human; D056566:Sirtuin 3; D037761:Sirtuins; D005947:Glucose