Kumagai Hiroshi, Kim Su-Jeong, Miller Brendan, Zempo Hirofumi, Tanisawa Kumpei, Natsume Toshiharu, Lee Shin Hyung, Wan Junxiang, Leelaprachakul Naphada, Kumagai Michi Emma, Ramirez Ricardo, Mehta Hemal H, Cao Kevin, Oh Tae Jung, Wohlschlegel James A, Sha Jihui, Nishida Yuichiro, Fuku Noriyuki, Dobashi Shohei, Miyamoto-Mikami Eri, Takaragawa Mizuki, Fuku Mizuho, Yoshihara Toshinori, Naito Hisashi, Kawakami Ryoko, Torii Suguru, Midorikawa Taishi, Oka Koichiro, Hara Megumi, Iwasaka Chiharu, Yamada Yosuke, Higaki Yasuki, Tanaka Keitaro, Yen Kelvin, Cohen Pinchas
The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan.
iScience. 2024 Oct 19;27(11):111212. doi: 10.1016/j.isci.2024.111212. eCollection 2024 Nov 15.
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.
MOTS-c是一种可改善新陈代谢的线粒体微小蛋白。在此，我们证明CK2是MOTS-c的直接功能性靶点。MOTS-c在无细胞系统中直接与CK2结合并激活它。给小鼠施用MOTS-c可预防骨骼肌萎缩并增强肌肉对葡萄糖的摄取，而抑制CK2活性则会减弱这些作用。有趣的是，MOTS-c的作用具有组织特异性。全身施用的MOTS-c与脂肪和肌肉中的CK2结合，但通过差异修饰与CK2相互作用的蛋白质，在肌肉中刺激CK2活性，而在脂肪中抑制其活性。值得注意的是，一种天然存在的MOTS-c变体，即K14Q MOTS-c，与CK2的结合减少，不能激活它或引发其效应。男性K14Q MOTS-c携带者以年龄和身体活动依赖的方式表现出更高的肌肉减少症和2型糖尿病（T2D）风险，而女性患T2D的风险则有年龄特异性降低。总之，这些发现提供了证据表明CK2是MOTS-c发挥作用所必需的。
