Evidence for a Mitochondrial Regulatory Pathway Defined by Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α, Estrogen-Related Receptor-α, and Mitofusin 2

Evidence for a Mitochondrial Regulatory Pathway Defined by Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α, Estrogen-Related Receptor-α, and Mitofusin 2 Francesc X. Soriano 1 , Marc Liesa 1 , Daniel Bach 1 , David C. Chan 2 , Manuel Palacín 1 and Antonio Zorzano 1 1 Institute for Research in Biomedicine (IRB), Scientific Park of Barcelona, and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain 2 Division of Biology, California Institute of Technology, Pasadena, California Address correspondence and reprint requests to Antonio Zorzano, Institute for Research in Biomedicine, IRB-Parc Científic de Barcelona,Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. E-mail: azorzano{at}pcb.ub.es Abstract Mitofusin 2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion and regulates mitochondrial metabolism in mammalian cells. Here, we show that Mfn2 gene expression is induced in skeletal muscle and brown adipose tissue by conditions associated with enhanced energy expenditure, such as cold exposure or β 3 -adrenergic agonist treatment. In keeping with the role of peroxisome proliferator–activated receptor-γ coactivator (PGC)-1α on energy expenditure, we demonstrate a stimulatory effect of PGC-1α on Mfn2 mRNA and protein expression in muscle cells. PGC-1α also stimulated the activity of the Mfn2 promoter, which required the integrity of estrogen-related receptor-α (ERRα)-binding elements located at −413/−398. ERRα also activated the transcriptional activity of the Mfn2 promoter, and the effects were synergic with those of PGC-1α. Mfn2 loss of function reduced the stimulatory effect of PGC-1α on mitochondrial membrane potential. Exposure to cold substantially increased Mfn2 gene expression in skeletal muscle from heterozygous Mfn2 knock-out mice, which occurred in the presence of higher levels of PGC-1α mRNA compared with control mice. Our results indicate the existence of a regulatory pathway involving PGC-1α, ERRα, and Mfn2. Alterations in this regulatory pathway may participate in the pathophysiology of insulin-resistant conditions and type 2 diabetes. Footnotes D.B. is currently affiliated with the School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. ERRα, estrogen-related receptor-α; COX-II, cytochrome c oxidase subunit-II; MEF2, myocyte enhancer factor-2; Mfn2, m