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Down‐regulation of Mitofusin2, a target gene of PPARδ, disrupts mitochondria network in the hearts of cardiomyocyte‐restricted PPARδ knockout mice
Author(s) -
Li Yuquan,
Yin Ran,
Broke Lawrence,
Floyd Donna,
Yang Qinglin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.629.5
Subject(s) - peroxisome proliferator activated receptor , knockout mouse , mitochondrion , biology , medicine , endocrinology , peroxisome , receptor , microbiology and biotechnology , genetics
Cardiomyocyte‐restricted PPARδ knockout in mice (CR‐PPARδ−/−) leads to depression of myocardial FAO and bioenergetics in the heart. A substantial loss of mitochondria network is one of the ultrastructural features in CR‐PPARδ−/− hearts. We hypothesized that mitofusin 2, a protein essential for mitochondrial networking is responsible for the loss of mitochondrial network in the CR‐PPARδ−/− hearts. Quantitative real‐time PCR revealed that mitofusin 2 transcript levels in the CR‐PPARδ−/− hearts were about 50 % of those in controls (n=4, P<0.05). Mitofusin 2 protein levels in CR‐PPARδ−/− hearts were also about 30% less than those in controlled hearts (n=4, P<0.05). Protein levels of mitochondrila marker proteins such as MTCO‐1 in the CR‐PPARδ−/− hearts were not changed. Since expression of PGC‐1 is not changed in CR‐PPARδ−/− hearts, we further assessed if PPARδ can directly regulate mitofusin 2 expression. We discovered a putative PPRE consensus sequence located at around −550 bp upstream of the mouse mitofusin 2 promoter. Using a LightShift chemiluminescent EMSA kit, we confirmed that the probe derived from a fragment of this putative −550 bp PPRE was strongly bound in nuclear protein. Therefore, we conclude that mitofusin 2 is a direct PPAR target gene. Its deficiency due to PPARδ knockout in cardiomyocyte contributes to the mitochondria abnormalities found in CR‐PPARδ−/− hearts.