Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2.
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 beta(3)-adrenergic agonist treatment. In keeping with the role of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha on energy expenditure, we demonstrate a stimulatory effect of PGC-1 alpha on Mfn2 mRNA and protein expression in muscle cells. PGC-1 alpha also stimulated the activity of the Mfn2 promoter, which required the integrity of estrogen-related receptor-alpha (ERR alpha)-binding elements located at -413/-398. ERR alpha also activated the transcriptional activity of the Mfn2 promoter, and the effects were synergic with those of PGC-1 alpha. Mfn2 loss of function reduced the stimulatory effect of PGC-1 alpha 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-1 alpha mRNA compared with control mice. Our results indicate the existence of a regulatory pathway involving PGC-1 alpha, ERR alpha, and Mfn2. Alterations in this regulatory pathway may participate in the pathophysiology of insulin-resistant conditions and type 2 diabetes.
Soriano
Francesc X
FX
Institute for Research in Biomedicine (IRB), Scientífic Park of Barcelona, Departament of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barelona, Spain.
Liesa
Marc
M
Bach
Daniel
D
Chan
David C
DC
Palacín
Manuel
M
Zorzano
Antonio
A
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003080:Cold Temperature; D004149:Dioxoles / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D020558:GTP Phosphohydrolases; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D004149:Dioxoles; D047628:Estrogen Receptor alpha; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human