p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria

J Biol Chem. 2016 Jun 10;291(24):12575-12585. doi: 10.1074/jbc.M115.695577. Epub 2016 Apr 8.


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.

Keywords: Shc; aging; diet; high fat diet resistance; insulin; lipid metabolism; longevity; mitochondria; p46Shc; thiolase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Fatty Acids
  • Mitochondrial Proteins
  • Protein Isoforms
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Acaa2 protein, mouse
  • Acetyl-CoA C-Acyltransferase