Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.

Abstract

P-bodies (PBs) and stress granules (SGs) are conserved, non-membranous cytoplasmic condensates of RNA-protein complexes. PBs are implicated in post-transcriptional regulation of gene expression through mRNA decay, translational repression and/or storage. Although much is known about the de novo formation of PBs and SGs involving liquid-liquid phase separation through multiple protein-protein and protein-RNA interactions, their subcellular localization and turnover mechanisms are less understood. Here, we report the presence of a subpopulation of PBs and SGs that are in proximity to ER-mitochondria contact sites (ERMCSs) in mammalian cells. Disruption of ERMCSs, achieved through depletion of ER-mitochondria tethering proteins, leads to the disappearance of PBs but not SGs. This effect can be reversed by inhibiting autophagy through both genetic and pharmacological means. Additionally, we find that the disruption of ERMCSs leads to cytosolic Ca2+-induced activation of CaMKK2 and AMP-activated protein kinase (AMPK), ultimately resulting in an autophagy-dependent decrease in PB abundance. Collectively, our findings unveil a mechanism wherein disturbances in ERMCSs induce autophagy-dependent loss of PBs via activation of the Ca2+-CaMKK2-AMPK pathway, thus potentially linking the dynamics and functions of ERMCS with post-transcriptional gene regulation.