Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis.
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 γ Coactivator (PGC-1α), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1α via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1α 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-1α 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 β-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-1α protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112;
Jun Hong
JH
Park
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112;
Hong-Jun
HJ
Kang
Molecular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
Yun Kyung
YK
Lee
Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Hyeog
H
Kang
Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA 70808; and.
Jihyun
J
Kim
Laboratory of Obesity and Aging Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Jay H
JH
Chung
Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA 70808; and.
Ji Suk
JS
Chang
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Alexandra C
AC
McPherron
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112; slee30@tulane.edu.
Sean Bong
SB
Lee
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D004734:Energy Metabolism; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011487:Protein Conformation; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D004272:DNA, Mitochondrial; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D005227:Fatty Acids; C513272:Fbxw7 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D010100:Oxygen
EWS; PGC-1alpha; energy metabolism; mitochondria homeostasis; protein stability