Mitochondria Control mTORC1 Activity Linked Compartmentalization of eIF4E to Regulate Extracellular Export of microRNAs

Abstract

Defective intracellular trafficking and export of microRNAs have been observed in growth retarded mammalian cells having impaired mitochondrial potential and dynamics. Uncoupling Protein 2 mediated depolarization of mitochondrial membrane also results in progressive sequestration of microRNAs with polysomes and lowered their release via extracellular vesicles. Interestingly, impaired miRNA-trafficking process in growth retarded human cells could be reversed in presence of Genipin an inhibitor of Uncoupling Protein 2. Mitochondrial detethering of endoplasmic reticulum, observed in mitochondria depolarized cells, found to be responsible for defective compartmentalization of translation initiation factor eIF4E to endoplasmic reticulum attached polysomes. It causes retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs with endoplasmic reticulum attached polysomes to restrict extracellular export of miRNAs. Reduced compartment specific activity of mTORC1 complex, the master regulator of protein synthesis, in mitochondria defective or ER- detethered cells, causes reduced phosphorylation of eIF4E-BP1 to prevent eIF-4E targeting to ER attached polysome and microRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine sub-cellular localization and export of microRNAs.