| First Author | Tomilov A | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 24 | Pages | 12575-85 |
| PubMed ID | 27059956 | Mgi Jnum | J:235036 |
| Mgi Id | MGI:5792643 | Doi | 10.1074/jbc.M115.695577 |
| Citation | Tomilov A, et al. (2016) p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria. J Biol Chem 291(24):12575-85 |
| abstractText | 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. |
