title: p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria.
abstract: Although the p46Shc isoform has been known to be mitochondrially localized for 11 years, its function in mitochondria has been a mystery. We confirmed p46Shc to be mitochondrially localized and showed that the major mitochondrial partner of p46Shc is the lipid oxidation enzyme 3-ketoacylCoA thiolase ACAA2, to which p46Shc binds directly and with a strong affinity. Increasing p46Shc expression inhibits, and decreasing p46Shc stimulates enzymatic activity of thiolase in vitro Thus, we suggest p46Shc to be a negative mitochondrial thiolase activity regulator, and reduction of p46Shc expression activates thiolase. This is the first demonstration of a protein that directly binds and controls thiolase activity. Thiolase was thought previously only to be regulated by metabolite balance and steady-state flux control. Thiolase is the last enzyme of the mitochondrial fatty acid beta-oxidation spiral, and thus is important for energy metabolism. Mice with reduction of p46Shc are lean, resist obesity, have higher lipid oxidation capacity, and increased thiolase activity. The thiolase-p46Shc connection shown here in vitro and in organello may be an important underlying mechanism explaining the metabolic phenotype of Shc-depleted mice in vivo.
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616.
authors.forename: Alexey
authors.initials: A
authors.lastname: Tomilov
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tomilova
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616; Department of Nutrition, University of California Davis, California 95616 and.
authors.forename: Kevork
authors.initials: K
authors.lastname: Hagopian
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616; Department of Public Health Sciences, University of California Davis, California 95616.
authors.forename: Kyoungmi
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO, Via Adamello, 1620139 Milan, Italy.
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: Department of Nutrition, University of California Davis, California 95616 and.
authors.forename: Fawaz
authors.initials: F
authors.lastname: Haj
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616; Department of Nutrition, University of California Davis, California 95616 and.
authors.forename: Jon
authors.initials: J
authors.lastname: Ramsey
authors.affiliation: Department of ‡Molecular Biosciences, University of California Davis, California 95616. Electronic address: gcortopassi@ucdavis.edu.
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D002460:Cell Line; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C000612344:Acaa2 protein, mouse; D000102:Acetyl-CoA C-Acyltransferase
keywords: Shc; aging; diet; high fat diet resistance; insulin; lipid metabolism; longevity; mitochondria; p46Shc; thiolase