安普克
AMP活化蛋白激酶
磷酸化
蛋白激酶A
线粒体
线粒体分裂
内分泌学
蛋白激酶B
mTORC1型
内科学
化学
细胞生物学
生物
医学
作者
Alexia Pearah,Balamurugan Ramatchandirin,Ting Liu,Risa M. Wolf,Akiko Ikeda,Sally Radovick,Hiromi Sesaki,Fredric E. Wondisford,Brian O’Rourke,Liang He
标识
DOI:10.1016/j.chembiol.2023.09.017
摘要
Impaired mitochondrial dynamics causes aging-related or metabolic diseases. Yet, the molecular mechanism responsible for the impairment of mitochondrial dynamics is still not well understood. Here, we report that elevated blood insulin and/or glucagon levels downregulate mitochondrial fission through directly phosphorylating AMPKα at S496 by AKT or PKA, resulting in the impairment of AMPK-MFF-DRP1 signaling and mitochondrial dynamics and activity. Since there are significantly increased AMPKα1 phosphorylation at S496 in the liver of elderly mice, obese mice, and obese patients, we, therefore, designed AMPK-specific targeting peptides (Pa496m and Pa496h) to block AMPKα1S496 phosphorylation and found that these targeting peptides can increase AMPK kinase activity, augment mitochondrial fission and oxidation, and reduce ROS, leading to the rejuvenation of mitochondria. Furthermore, these AMPK targeting peptides robustly suppress liver glucose production in obese mice. Our data suggest these targeting peptides are promising therapeutic agents for improving mitochondrial dynamics and activity and alleviating hyperglycemia in elderly and obese patients.
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