Park 2015 Proc Natl Acad Sci USA

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Park JH, Kang HJ, Lee YK, Kang H, Kim J, Chung JH, Chang JS, McPherron AC, Lee SB (2015) Inactivation of EWS reduces PGC-1α protein stability and mitochondrial homeostasis. Proc Natl Acad Sci USA 112:6074-9.

» PMID: 25918410

Park JH, Kang HJ, Lee YK, Kang H, Kim J, Chung JH, Chang JS, McPherron AC, Lee SB (2015) Proc Natl Acad Sci USA

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.

Keywords: EWS, PGC-1alpha, Energy metabolism, Mitochondria homeostasis, Protein stability, Adipocyte

O2k-Network Lab: US LA Baton Rouge Noland RC

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cancer 

Organism: Mouse  Tissue;cell: Fat  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k