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

• DOI: 10.1083/jcb.202006049
• Publication Date: 2021-10-10T22:26:52Z
• Authors: Nicolas Rabas; Sarah Palmer; Louise Mitchell; Shehab Ismail; Andrea Gohlke; Joel S. Riley; Stephen W.G. Tait; Payam Gammage; Leandro Lemgruber...; Iain R. Macpherson; Jim C. Norman
• Keywords: Glutaminolysis

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