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Systemic factors, such as lipid-enriched environments [as low-density lipoprotein (LDL)-cholesterol], favor breast cancer, including triple-negative breast cancer (TNBC) metastasis formation. Mitochondria metabolism impacts TNBC invasive behavior but its involvement in a lipid-enriched setting is undisclosed. Here we show that LDL increases lipid droplets, induces CD36 and augments TNBC cells migration and invasion in vivo and in vitro. LDL induces higher mitochondrial mass and network spread in migrating cells, in an actin remodeling-dependent manner, and transcriptomic and energetic analyses revealed that LDL renders TNBC cells dependent on fatty acids (FA) usage for mitochondrial respiration. Indeed, engagement on FA transport into the mitochondria is required for LDL-induced migration and mitochondrial remodeling. Mechanistically, LDL treatment leads to mitochondrial long-chain fatty acid accumulation and increased reactive oxygen species (ROS) production. Importantly, CD36 or ROS blockade abolished LDL-induced cell migration and mitochondria metabolic adaptations. Our data suggest that LDL induces TNBC cells migration by reprogramming mitochondrial metabolism, revealing a new vulnerability in metastatic breast cancer.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>LDL induces breast cancer cell migration that relies on CD36 for mitochondrial metabolism and network remodeling, providing an antimetastatic metabolic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2767-9764.crc-22-0394","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T18:43:45Z","timestamp":1680633825000},"page":"709-724","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mitochondrial Metabolism Drives Low-density Lipoprotein-induced Breast Cancer Cell 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University of Lisbon, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-5204","authenticated-orcid":true,"given":"Teresa L.","family":"Serafim","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9474-2437","authenticated-orcid":true,"given":"Ana Patr\u00edcia","family":"Lopes","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6413-7186","authenticated-orcid":true,"given":"Diogo","family":"Coutinho","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0074-0741","authenticated-orcid":true,"given":"Filipa S.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"1Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisbon, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5357-3601","authenticated-orcid":true,"given":"Ros\u00e1rio M.","family":"Domingues","sequence":"additional","affiliation":[{"name":"3Mass Spectrometry Center, QOPNA, University of Aveiro, Aveiro, Portugal."},{"name":"4Department of Chemistry and CESAM&ECOMARE, University of Aveiro, Aveiro, Portugal."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8060-7675","authenticated-orcid":true,"given":"Pedro","family":"Domingues","sequence":"additional","affiliation":[{"name":"3Mass Spectrometry Center, QOPNA, University of Aveiro, Aveiro, 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