ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue
Hironori Kato, Kohki Okabe, Masato Miyake, Kazuki Hattori, Tomohiro Fukaya, Kousuke Tanimoto, Beini Shi, Mariko Mizuguchi, Satoru Torii, Satoko Arakawa, Masaya Ono, Yusuke Saito, Takashi Sugiyama, Takashi Funatsu, Katsuaki Sato, Shigeomi Shimizu, Seiichi Oyadomari, Hidenori Ichijo, Hisae Kadowaki, Hideki Nishitoh
Abstract
Mitochondria play a central role in the function of brown adipocytes (BAs). Although mitochondrial biogenesis, which is indispensable for thermogenesis, is regulated by coordination between nuclear DNA transcription and mitochondrial DNA transcription, the molecular mechanisms of mitochondrial development during BA differentiation are largely unknown. Here, we show the importance of the ER-resident sensor PKR-like ER kinase (PERK) in the mitochondrial thermogenesis of brown adipose tissue. During BA differentiation, PERK is physiologically phosphorylated independently of the ER stress. This PERK phosphorylation induces transcriptional activation by GA-binding protein transcription factor α subunit (GABPα), which is required for mitochondrial inner membrane protein biogenesis, and this novel role of PERK is involved in maintaining the body temperatures of mice during cold exposure. Our findings demonstrate that mitochondrial development regulated by the PERK-GABPα axis is indispensable for thermogenesis in brown adipose tissue.