ACAA2
3-ketoacyl-CoA thiolase, mitochondrial (EC 2.3.1.16) (Acetyl-CoA acetyltransferase) (EC 2.3.1.9) (Acetyl-CoA acyltransferase) (Acyl-CoA hydrolase, mitochondrial) (EC 3.1.2.-) (EC 3.1.2.1) (EC 3.1.2.2) (Beta-ketothiolase) (Mitochondrial 3-oxoacyl-CoA thiolase) (T1)
Publications[править]
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
Keywords
- Shc
- aging
- diet
- high fat diet resistance
- insulin
- lipid metabolism
- longevity
- mitochondria
- p46Shc
- thiolase