Inhibitory effect of p53 on mitochondrial content and function during adipogenesis

• Published in: Biochemical and biophysical research communications 2014-03, Vol.446 (1), p.91-97
• Main Authors: Okita, Naoyuki, Ishikawa, Natsumi, Mizunoe, Yuhei, Oku, Misako, Nagai, Wataru, Suzuki, Yuki, Matsushima, Shingo, Mikami, Kentaro, Okado, Hitoshi, Sasaki, Takashi, Higami, Yoshikazu
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes - cytology; Adipocytes - metabolism; Adipogenesis; Adipogenesis - genetics; Adipogenesis - physiology; Animals; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Line; Cell Lineage - genetics; Cell Lineage - physiology; Cells, Cultured; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression; Gene Knockdown Techniques; Genes, p53; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial biogenesis; Myoblasts, Skeletal - cytology; Myoblasts, Skeletal - metabolism; p53; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Ppargc1a; Transcription Factors - genetics; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.02.059

•We focused on mitochondrial regulation of p53 in adipocytes and myotubes.•In 3T3-L1 preadipocytes, p53 upregulation downregulates the expression of Ppargc1a.•p53KD 3T3-L1 cells showed increase in mt content and activity during adipogenesis.•p53 is an inhibitory factor of mitochondrial regulation in adipocyte lineage. The p53 protein is known as a guardian of the genome and is involved in energy metabolism. Since the metabolic system is uniquely regulated in each tissue, we have anticipated that p53 also would play differential roles in each tissue. In this study, we focused on the functions of p53 in white adipose tissue (adipocytes) and skeletal muscle (myotubes), which are important peripheral tissues involved in energy metabolism. We found that in 3T3-L1 preadipocytes, but not in C2C12 myoblasts, p53 stabilization or overexpression downregulates the expression of Ppargc1a, a master regulator of mitochondrial biogenesis. Next, by using p53-knockdown C2C12 myotubes or 3T3-L1 preadipocytes, we further examined the relationship between p53 and mitochondrial regulation. In C2C12 myoblasts, p53 knockdown did not significantly affect Ppargc1a expression and mtDNA, but did suppress differentiation to myotubes, as previously reported. However, in 3T3-L1 preadipocytes and mouse embryonic fibroblasts, p53 downregulation enhanced both differentiation into adipocytes and mitochondrial DNA content. Furthermore, p53-depleted 3T3-L1 cells showed increase in mitochondrial proteins and enhancement of both Citrate Synthase and Complex IV activities during adipogenesis. These results show that p53 differentially regulates cell differentiation and mitochondrial biogenesis between adipocytes and myotubes, and provide evidence that p53 is an inhibitory factor of mitochondrial regulation in adipocyte lineage.