Blocking AMPKaS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity
Blocking AMPKaS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity
复制标题
阻断 AMPKaS496 磷酸化可改善衰老和肥胖症中的线粒体动力学和高血糖
DOI：
10.1016/j.chembiol.2023.09.017
复制
发表时间：
2023-12-21
影响因子：
8.6
通讯作者：
He，Ling
中科院分区：
文献类型：
--
作者：
Pearah，Alexia;Ramatchandirin，Balamurugan;He，Ling
线粒体动力学受损会导致衰老相关疾病或代谢性疾病。然而，线粒体动力学受损的分子机制仍然没有得到很好的理解。在这里，我们报告了升高的血液胰岛素和/或胰高血糖素水平通过AKT或PKA直接磷酸化AMPKα在S496下调线粒体分裂，导致AMPK-MFF-DRP 1信号传导和线粒体动力学和活性受损。由于老年小鼠、肥胖小鼠和肥胖患者肝脏中AMPKα1在S496处磷酸化显著增加，因此，我们设计了AMPK特异性靶向肽（Pa 496 m和Pa 496 h）阻断AMPKα 1 S496磷酸化，发现这些靶向肽可以增加AMPK激酶活性，增加线粒体分裂和氧化，减少ROS，导致线粒体再生。此外，这些AMPK靶向肽强烈抑制肥胖小鼠的肝脏葡萄糖产生。我们的数据表明，这些靶向肽是有前途的治疗剂，用于改善线粒体动力学和活性，并减轻老年和肥胖患者的高血糖症。
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.