p46Shc inhibits thiolase and lipid oxidation in mitochondria

Alexey Tomilov, Natalia Tomilova, Yuxi Shan, Kevork Hagopian, Ahmed Bettaieb, Kyoungmi Kim, Pier Giuseppe Pelicci, Fawaz Haj, Jon J Ramsey, Gino A Cortopassi

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)12575-12585
Number of pages11
JournalJournal of Biological Chemistry
Issue number24
StatePublished - Jun 10 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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