The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses

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.

Automated summary

Energy deprivation triggers mitochondrial fission and autophagy, while also increasing the number of mitochondrial-associated ER membranes (MAMs) through AMP-activated protein kinase (AMPK) activity. AMPK translocates to MAMs and interacts with mitofusin 2 (MFN2) during energy stress, regulating autophagy and MAM dynamics. MFN2 plays a critical role in cell survival and function under energy stress, highlighting the importance of the AMPK-MFN2 pathway in cellular stress response.