The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses
The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses
复制标题
AMPK-MFN2 轴调节能量应激诱导的 MAM 动力学和自噬。
DOI：
10.1080/15548627.2020.1749490
复制
发表时间：
2020-04-20
期刊：
影响因子：
13.3
通讯作者：
Feng, Du
中科院分区：
文献类型：
--
作者：
Hu, Yongquan;Chen, Hao;Feng, Du
能量剥夺激活细胞能量传感器AMP活化蛋白激酶（AMPK），其进而诱导巨自噬/自噬。线粒体相关的内质网膜（MAM）在线粒体分裂和自噬中起关键作用，线粒体融合蛋白MFN 2（mitofusin 2）束缚MAM，但AMPK和MFN 2响应能量应激调节自噬的机制尚不清楚。在这里，我们发现能量应激不仅触发线粒体分裂和自噬，更重要的是增加MAMs的数量，这一过程需要AMPK。有趣的是，在能量胁迫下，大量的AMPK从细胞质易位到MAM和线粒体分裂发生的线粒体。出乎意料的是，AMPK直接与MFN 2相互作用。与野生型MEF（WT MEF）相比，缺乏MFN 2（mfn 2（-/-））的小鼠胚胎成纤维细胞（MEF）的自噬能力在能量应激下显着减弱，而MFN 2在mfn 2（-/-）细胞中的重新表达挽救了这些细胞的自噬缺陷。在MFN 2缺陷型细胞中，MAMs的丰度也大大降低。功能实验表明，缺乏MFN 2而不缺乏MFN 1的细胞的耗氧速率和糖酵解功能明显减弱，MFN 2对能量应激下的细胞存活至关重要。总之，我们的研究建立了能量传感器AMPK和MAM系链MFN 2之间的分子联系，并揭示了AMPK和MFN 2在能量应激诱导的自噬和MAM动力学中的重要作用。
Energy deprivation activates the cellular energy sensor AMP-activated protein kinase (AMPK), which in turn induces macroautophagy/autophagy. The mitochondrial-associated ER membrane (MAM) plays a key role in mitochondrial division and autophagy, and the mitochondrial fusion protein MFN2 (mitofusin 2) tethers the MAM, but the mechanism by which AMPK and MFN2 regulate autophagy in response to energy stress remains unclear. Here, we found that energy stress not only triggers mitochondrial fission and autophagy, but more importantly increases the number of MAMs, a process that requires AMPK. Interestingly, under energy stress, considerable amounts of AMPK translocate from cytosol to the MAM and the mitochondrion as mitochondrial fission occurs. Unexpectedly, AMPK interacts directly with MFN2. The autophagic ability of mouse embryonic fibroblasts (MEFs) lacking MFN2 (mfn2(-/-)) is significantly attenuated in response to energy stress as compared to wild-type MEFs (WT MEFs), while re-expression of MFN2 in mfn2(-/-) cells rescues the autophagy defects of these cells. The abundance of MAMs is also greatly reduced in MFN2-deficient cells. Functional experiments show that the oxygen consumption rate and the glycolytic function of cells lacking MFN2 but not MFN1 are obviously attenuated, and MFN2 is important for cell survival under energy stress. In conclusion, our study establishes the molecular link between the energy sensor AMPK and the MAM tether MFN2, and reveals the important role of AMPK and MFN2 in energy stress-induced autophagy and MAM dynamics.