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Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that H\u00fcrthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR\u2013Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I\u2013mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects.<\/jats:p>\n                    <jats:p>See related article by Gopal et al., p. 1904.<\/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-22-0982","type":"journal-article","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T13:27:45Z","timestamp":1685626065000},"page":"1884-1903","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in H\u00fcrthle Cell Carcinoma of the Thyroid"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2239-9975","authenticated-orcid":false,"given":"Anderson R.","family":"Frank","sequence":"first","affiliation":[{"name":"1Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3113-8910","authenticated-orcid":false,"given":"Vicky","family":"Li","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1236-5317","authenticated-orcid":false,"given":"Spencer D.","family":"Shelton","sequence":"additional","affiliation":[{"name":"3Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0220-9329","authenticated-orcid":false,"given":"Jiwoong","family":"Kim","sequence":"additional","affiliation":[{"name":"4Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9148-6100","authenticated-orcid":false,"given":"Gordon M.","family":"Stott","sequence":"additional","affiliation":[{"name":"5Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9639-7249","authenticated-orcid":false,"given":"Leonard M.","family":"Neckers","sequence":"additional","affiliation":[{"name":"6Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9456-1762","authenticated-orcid":false,"given":"Yang","family":"Xie","sequence":"additional","affiliation":[{"name":"4Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1894-5742","authenticated-orcid":false,"given":"Noelle S.","family":"Williams","sequence":"additional","affiliation":[{"name":"2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-1742","authenticated-orcid":false,"given":"Prashant","family":"Mishra","sequence":"additional","affiliation":[{"name":"3Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"7Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"8Deparment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8466-2199","authenticated-orcid":false,"given":"David G.","family":"McFadden","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas."},{"name":"7Harold C. 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