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Mitochondria control mTORC1 activity-linked compartmentalization of eIF4E to regulate extracellular export of microRNAs

Chatterjee, Susanta and Chakrabarty, Yogaditya and Banerjee, Saikat and Ghosh, Souvik and Bhattacharyya, Suvendra N. (2020) Mitochondria control mTORC1 activity-linked compartmentalization of eIF4E to regulate extracellular export of microRNAs. Journal of Cell Science, 133 (24). Art. No. jcs250241. ISSN 0021-9533. https://resolver.caltech.edu/CaltechAUTHORS:20210212-094310972

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Abstract

Defective intracellular trafficking and export of microRNAs (miRNAs) have been observed in growth-retarded mammalian cells having impaired mitochondrial potential and dynamics. Here, we found that uncoupling protein 2 (Ucp2)-mediated depolarization of mitochondrial membrane also results in progressive sequestration of miRNAs within polysomes and lowers their release via extracellular vesicles. Interestingly, the impaired miRNA-trafficking process in growth-retarded human cells could be reversed in the presence of Genipin, an inhibitor of Ucp2. Mitochondrial detethering of endoplasmic reticulum (ER), observed in cells with depolarized mitochondria, was found to be responsible for defective compartmentalization of translation initiation factor eIF4E to polysomes attached to ER. This caused a retarded translation process accompanied by enhanced retention of miRNAs and target mRNAs within ER-attached polysomes to restrict extracellular export of miRNAs. Reduced compartment-specific activity of the mammalian target of rapamycin complex 1 (mTORC1), the master regulator of protein synthesis, in cells with defective mitochondria or detethered ER, caused reduced phosphorylation of eIF4E-BP1 and prevented eIF4E targeting to ER-attached polysomes and miRNA export. These data suggest how mitochondrial membrane potential and dynamics, by affecting mTORC1 activity and compartmentalization, determine the subcellular localization and export of miRNAs.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1242/jcs.250241DOIArticle
https://jcs.biologists.org/content/133/24/jcs250241.supplementalPublisherSupplementary Information
ORCID:
AuthorORCID
Chatterjee, Susanta0000-0003-0396-2670
Chakrabarty, Yogaditya0000-0002-3230-9251
Banerjee, Saikat0000-0001-9697-3824
Ghosh, Souvik0000-0003-4152-4460
Bhattacharyya, Suvendra N.0000-0001-9697-3824
Additional Information:© 2020. Published by The Company of Biologists Ltd. Received 16 June 2020; Accepted 17 November 2020. We acknowledge Witold Filipowicz, Sanjay Ghosh, Krishna Das Saha and Subhas C. Biswas for different plasmid constructs, reagents and antibodies. S.N.B. is supported by The Swarnajayanti Fellowship (SJF/LS-03/2014-15) from Department of Scientific and Industrial Research, Ministry of Science and Technology, India, while Y.C., S.B., S.C. and S.G. received their support from Council of Scientific and Industrial Research, India (CSIR). We are supported by funds from High Risk High Reward Project Grant (HRR/2016/00093), Science and Engineering Research Board, Dept. of Science and Technology, Govt. of India and an Indo-French Centre for the Promotion of Advanced Research (CEFIPRA) Project Grant (6003-J). The authors declare no competing or financial interests. Author contributions: Conceptualization: S.C., Y.C., S.B., S.G., S.N.B.; Methodology: S.C., Y.C., S.B., S.N.B.; Software: Y.C., S.B., S.G.; Validation: Y.C., S.G.; Formal analysis: S.G., S.N.B.; Investigation: S.C., Y.C., S.B., S.G.; Data curation: S.C., S.N.B.; Writing - original draft: S.N.B.; Visualization: S.N.B.; Supervision: S.N.B.; Project administration: S.N.B.; Funding acquisition: S.N.B.
Funders:
Funding AgencyGrant Number
Department of Science and Technology (India)SJF/LS-03/2014-15
Council of Science and Industrial Research (India)UNSPECIFIED
Science and Engineering Research Board (SERB)HRR/2016/00093
Indo-French Centre for the Promotion of Advanced Research6003-J
Subject Keywords:miRNA, Processing bodies, P-body, Mitochondria, Polysome, Extracellular vesicles, Exosomes, eIF4E, mTORC1
Issue or Number:24
Record Number:CaltechAUTHORS:20210212-094310972
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210212-094310972
Official Citation:Mitochondria control mTORC1 activity-linked compartmentalization of eIF4E to regulate extracellular export of microRNAs. Susanta Chatterjee, Yogaditya Chakrabarty, Saikat Banerjee, Souvik Ghosh, Suvendra N. Bhattacharyya. Journal of Cell Science 2020 133: jcs250241 doi: 10.1242/jcs.250241 Published 29 December 2020
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108032
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Feb 2021 18:04
Last Modified:12 Feb 2021 18:04

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