title: Estrogen-related receptor alpha is essential for the expression of antioxidant protection genes and mitochondrial function.
abstract: Estrogen-related receptor alpha (ERRalpha) is an important mediator of mitochondrial biogenesis and function. To investigate the transcriptional network controlling these phenomena, we investigated mitochondrial gene expression in embryonic fibroblasts isolated from ERRalpha null mice. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) stimulated mitochondrial gene expression program in control cells, but not in the ERRalpha null cells. Interestingly, the induction of levels of mitochondrial oxidative stress protection genes in response to increased PGC-1alpha levels was dependent on ERRalpha. Furthermore, we found that the PGC-1alpha-mediated induction of estrogen-related receptor gamma and nuclear respiratory factor 2 (NRF-2), was dependent on the presence of ERRalpha. Basal levels of NRF-2 were decreased in the absence of ERRalpha. The absence of ERRalpha resulted in a decrease in citrate synthase enzyme activity in response to PGC-1alpha overexpression. Our results indicate an essential role for ERRalpha as a key regulator of oxidative metabolism.
authors.affiliation: Diabetes and Metabolism Disease Area, Novartis Institutes of BioMedical Research Institutes, 100 Technology Square, Cambridge, MA 02139, USA. shamina.rangwala@novartis.com
authors.forename: Shamina M
authors.initials: SM
authors.lastname: Rangwala
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Loren
authors.initials: L
authors.lastname: Lindsley
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.forename: Stacey
authors.initials: S
authors.lastname: Shaughnessy
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Daniels
authors.forename: Joseph
authors.initials: J
authors.lastname: Szustakowski
authors.forename: N R
authors.initials: NR
authors.lastname: Nirmala
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Wu
authors.forename: Susan C
authors.initials: SC
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000975:Antioxidants; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human