PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness
| Autor: | Nicolas Rabas, Payam A. Gammage, Sarah Palmer, Louise Mitchell, Shehab Ismail, Stephen W.G. Tait, Joel S. Riley, Jim C. Norman, Iain R. Macpherson, Andrea Gohlke, Leandro Lemgruber Soares |
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| Rok vydání: | 2021 |
| Předmět: |
Endosome
INVASION Cell Endosomes Mitochondrion Biology Receptors Metabotropic Glutamate DNA Mitochondrial UBIQUITIN rab27 GTP-Binding Proteins Article Mitochondrial Proteins Extracellular Vesicles MITOCHONDRIA Cell Line Tumor DNA Packaging medicine Humans Neoplasm Invasiveness Receptor Cancer EXOSOMES Science & Technology Glutaminolysis Tetraspanin 30 PLATFORM Cell Biology Mitochondria Cell Metabolism Cell Death and Autophagy Cell biology RECEPTORS medicine.anatomical_structure Toll-Like Receptor 9 METASTASIS CELLS Cancer cell Metabotropic glutamate receptor 3 Cisplatin Life Sciences & Biomedicine Protein Kinases Intracellular |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Rabas et al. describe a novel means of intercellular communication in which processes evoked to mitigate cytotoxicity in metabolically stressed cells can promote PINK1-dependent packaging of mitochondrial DNA into exosomes to evoke invasive behavior in other cells. 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. |
| Databáze: | OpenAIRE |
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