PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness

Rabas, N. et al. (2021) PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness. Journal of Cell Biology, 220(12), e202006049. (doi: 10.1083/jcb.202006049) (PMID:34623384) (PMCID:PMC8641410)

Abstract

The cystine-glutamate antiporter, xCT, supports a glutathione synthesis program enabling cancer cells to cope with metabolically stressful microenvironments. Up-regulated xCT, in combination with glutaminolysis, leads to increased extracellular glutamate, which promotes invasive behavior by activating metabotropic glutamate receptor 3 (mGluR3). Here we show that activation of mGluR3 in breast cancer cells activates Rab27-dependent release of extracellular vesicles (EVs), which can transfer invasive characteristics to “recipient” tumor cells. These EVs contain mitochondrial DNA (mtDNA), which is packaged via a PINK1-dependent mechanism. We highlight mtDNA as a key EV cargo necessary and sufficient for intercellular transfer of invasive behavior by activating Toll-like receptor 9 in recipient cells, and this involves increased endosomal trafficking of pro-invasive receptors. We propose that an EV-mediated mechanism, through which altered cellular metabolism in one cell influences endosomal trafficking in other cells, is key to generation and dissemination of pro-invasive microenvironments during mammary carcinoma progression.

• Item Type: Articles
• Additional Information: This work was funded by Cancer Research UK and Breast Cancer Now. We acknowledge the Cancer Research UK Glasgow Centre (C596/A18076) and the Biostatistics Unit facilities at the Cancer Research UK Beatson Institute (C596/A17196).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Palmer, Dr Sarah and Gammage, Dr Payam and MacPherson, Professor Iain and Tait, Professor Stephen and Norman, Professor James and Mitchell, Mrs Louise and Rabas, Nicolas and Riley, Dr Joel and Lemgruber Soares, Dr Leandro and Ismail, Dr Shehab
• Authors: Rabas, N., Palmer, S., Mitchell, L., Ismail, S., Gohlke, A., Riley, J. S., Tait, S. W.G., Gammage, P., Lemgruber Soares, L., MacPherson, I. R., and Norman, J. C.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Cell Biology
• Publisher: Rockefeller University Press
• ISSN: 0021-9525
• ISSN (Online): 1540-8140
• Published Online: 08 October 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Journal of Cell Biology 220(12): e202006049
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190874		CR-UK Centre renewal	Karen Vousden	Cancer Research UK (CRUK)	C596/A18076	Institute of Cancer Sciences