{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:02:34Z","timestamp":1793138554520,"version":"4.5.0"},"reference-count":77,"publisher":"American Association for Cancer Research (AACR)","issue":"8","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":64,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ruane Gift"},{"name":"Bertarelli Rare Cancer Fund","award":["FP&#x2010"],"award-info":[{"award-number":["FP&#x2010"]}]},{"name":"Bertarelli Rare Cancer Fund","award":["0034304"],"award-info":[{"award-number":["0034304"]}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["K00CA212468"],"award-info":[{"award-number":["K00CA212468"]}]},{"name":"National Cancer Institute","award":["K12CA087723"],"award-info":[{"award-number":["K12CA087723"]}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Oncocytic (H\u00fcrthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR\u2013Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR\u2013Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC.<\/jats:p>\n                    <jats:p>See related article by Frank et al., p. 1884.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 1749<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-0976","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T13:27:57Z","timestamp":1685626077000},"page":"1904-1921","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Effectors Enabling Adaptation to Mitochondrial Complex I Loss in H\u00fcrthle Cell Carcinoma"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2861-2071","authenticated-orcid":false,"given":"Raj K.","family":"Gopal","sequence":"first","affiliation":[{"name":"1Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts."},{"name":"2Broad Institute of MIT and Harvard, Cambridge, Massachusetts."},{"name":"3Department of Medicine, Massachusetts General Hospital, Boston, \u00adMassachusetts."},{"name":"4Cancer Center, Massachusetts General Hospital, Boston, Massachusetts."},{"name":"5Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2846-8716","authenticated-orcid":false,"given":"Venkata R.","family":"Vantaku","sequence":"additional","affiliation":[{"name":"5Harvard Medical School, Boston, Massachusetts."},{"name":"6Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8369-9835","authenticated-orcid":false,"given":"Apekshya","family":"Panda","sequence":"additional","affiliation":[{"name":"1Howard Hughes Medical Institute and Department of 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