{"doi":"10.1083/jcb.202006049","title":"PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness","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.","journal":"The Journal of Cell Biology","year":2021,"id":147950,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":141,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":629730,"name":"Sarah E. Palmer","orcid":"0000-0002-7541-406X","position":1,"is_corresponding":false},{"id":629731,"name":"Louise Mitchell","orcid":"0009-0004-3173-5074","position":2,"is_corresponding":false},{"id":629732,"name":"Shehab Ismail","orcid":"0000-0002-4150-1077","position":3,"is_corresponding":false},{"id":629733,"name":"Andrea Gohlke","orcid":"0000-0002-5447-5453","position":4,"is_corresponding":false},{"id":629734,"name":"Joel S. Riley","orcid":"0000-0001-9170-5716","position":5,"is_corresponding":false},{"id":282047,"name":"Stephen W. G. Tait","orcid":"0000-0001-7697-132X","position":6,"is_corresponding":false},{"id":629735,"name":"Payam A. Gammage","orcid":"0000-0003-1968-1726","position":7,"is_corresponding":false},{"id":282046,"name":"Leandro Lemgruber","orcid":"0000-0003-2832-6806","position":8,"is_corresponding":false},{"id":629736,"name":"Iain R. Macpherson","orcid":"0000-0003-4295-8885","position":9,"is_corresponding":false},{"id":314708,"name":"Jim C. Norman","orcid":"0000-0002-0098-3014","position":10,"is_corresponding":false},{"id":629729,"name":"Nicolas Rabas","orcid":"0000-0002-8118-8134","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:42:41.063423Z","pmid":"34623384","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}