| First Author | Park JH | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 19 | Pages | 6074-9 |
| PubMed ID | 25918410 | Mgi Jnum | J:221663 |
| Mgi Id | MGI:5641289 | Doi | 10.1073/pnas.1504391112 |
| Citation | Park JH, et al. (2015) Inactivation of EWS reduces PGC-1alpha protein stability and mitochondrial homeostasis. Proc Natl Acad Sci U S A 112(19):6074-9 |
| abstractText | EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor gamma Coactivator (PGC-1alpha), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1alpha via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1alpha and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1alpha expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid beta-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1alpha protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation. |
