Peroxisome proliferator-activated receptor delta regulates mitofusin 2 expression in the heart.
Mitofusin 2 (Mfn2) has been proposed as an important mitochondrial protein in maintaining mitochondrial network and bioenergetics. Mfn2 is highly expressed in the heart, but is downregulated in response to hypertrophic stimuli. However, little is known about how Mfn2's expression is regulated in cardiomyocytes. Here, we have investigated how Mfn2 expression in the heart responds to fasting condition and determined if Mfn2 is one of those PPARdelta-selective target genes that are involved in myocardial energy metabolism. Fasting for 48 h in mice led to a robust increase of Mfn2 expression in the heart. On the other hand, cardiomyocyte-restricted PPARdelta deficiency in mice led to substantially diminished cardiac expression of Mfn2 transcript and protein compared to that of controls. Fasting induced cardiac expression of Mfn2 was blunted in cardiomyocyte-restricted PPARdelta deficient hearts. Moreover, PPARdelta-selective ligand treatment in cultured cardiomyocytes induced elevated Mfn2 expression. A functional PPRE consensus sequence located at -837 to -817 bp upstream of the mouse Mfn2 promoter was identified and confirmed by Electrophoretic Mobility Shift Assays and Luciferase Promoter Reporter Assays. We conclude that Mfn2 is a PPARdelta-selective target, which may play an important role in regulating myocardial energy homeostasis.
Li
Yuquan
Y
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-3360, USA.
Yin
Ran
R
Liu
Jian
J
Wang
Peiyong
P
Wu
Sijie
S
Luo
Jinwen
J
Zhelyabovska
Olga
O
Yang
Qinglin
Q
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005215:Fasting / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors; D010636:Phenols; D013438:Sulfhydryl Compounds
D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D047494:PPAR delta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013844:Thiazoles; D015534:Trans-Activators; D014157:Transcription Factors; C485290:Ppargc1a protein, mouse; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C488751:Mfn2 protein, mouse; C489710:Mfn2 protein, rat