Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis.

Abstract

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.

• Authors: Jun Hong Park, Hong-Jun Kang, Yun Kyung Lee, Hyeog Kang, Jihyun Kim, Jay H Chung, Ji Suk Chang, Alexandra C McPherron, Sean Bong Lee
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 19 Pg. 6074-9 (May 12 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25918410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• F-Box Proteins
• F-Box-WD Repeat-Containing Protein 7
• Fatty Acids
• Fbxw7 protein, mouse
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• RNA-Binding Protein EWS
• Transcription Factors
• Ubiquitin
• Ubiquitin-Protein Ligases
• Oxygen

Topics

• Adipose Tissue, Brown (metabolism)
• Animals
• DNA, Mitochondrial (metabolism)
• Energy Metabolism
• F-Box Proteins (metabolism)
• F-Box-WD Repeat-Containing Protein 7
• Fatty Acids (chemistry, metabolism)
• Gene Expression Profiling
• HEK293 Cells
• Homeostasis
• Humans
• Liver (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron, Transmission
• Mitochondria (metabolism)
• Muscle, Skeletal (metabolism)
• Oxygen (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Protein Conformation
• RNA-Binding Protein EWS (antagonists & inhibitors, metabolism)
• Transcription Factors (metabolism)
• Ubiquitin (chemistry)
• Ubiquitin-Protein Ligases (metabolism)