Article
Author: Miller, Brendan ; Mehta, Hemal H. ; Kumagai, Hiroshi ; Oh, Tae Jung ; Iwasaka, Chiharu ; Wan, Junxiang ; Sha, Jihui ; Zempo, Hirofumi ; Lee, Shin Hyung ; Oka, Koichiro ; Leelaprachakul, Naphada ; Higaki, Yasuki ; Wohlschlegel, James A. ; Tanaka, Keitaro ; Dobashi, Shohei ; Cao, Kevin ; Yamada, Yosuke ; Yen, Kelvin ; Kumagai, Michi Emma ; Ramirez, Ricardo ; Naito, Hisashi ; Takaragawa, Mizuki ; Cohen, Pinchas ; Hara, Megumi ; Mehta, Hemal H ; Natsume, Toshiharu ; Wohlschlegel, James A ; Miyamoto-Mikami, Eri ; Midorikawa, Taishi ; Tanisawa, Kumpei ; Fuku, Mizuho ; Yoshihara, Toshinori ; Nishida, Yuichiro ; Fuku, Noriyuki ; Kawakami, Ryoko ; Kim, Su-Jeong ; Torii, Suguru
MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.