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3-ketoacyl-CoA thiolase, mitochondrial (EC (Acetyl-CoA acetyltransferase) (EC (Acetyl-CoA acyltransferase) (Acyl-CoA hydrolase, mitochondrial) (EC 3.1.2.-) (EC (EC (Beta-ketothiolase) (Mitochondrial 3-oxoacyl-CoA thiolase) (T1)


p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria.

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.

MeSH Terms

  • Acetyl-CoA C-Acyltransferase
  • Animals
  • Binding, Competitive
  • Blotting, Western
  • Cell Line
  • Energy Metabolism
  • Fatty Acids
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lipid Metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria
  • Mitochondrial Proteins
  • NIH 3T3 Cells
  • Oxidation-Reduction
  • Protein Binding
  • Protein Isoforms
  • RNA Interference
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1


  • Shc
  • aging
  • diet
  • high fat diet resistance
  • insulin
  • lipid metabolism
  • longevity
  • mitochondria
  • p46Shc
  • thiolase