ArticleCancer discovery2023
Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- Genomics and Multi-Omics to Guide Clinical Management in Thyroid Cancer.International journal of molecular sciences · 2026Review
- Mitochondrial transfer technologies with molecular insights into clinical applications.Stem cells (Dayton, Ohio) · 2026Review
- Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.Science advances · 2026Article
- Mitochondrial DNA mutations and intercellular mitochondrial transfer in cancer: mechanisms, biological effects, and clinical potential.Biomarker research · 2026Review
- Article
- Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.bioRxiv : the preprint server for biology · 2025Article
- Review
- GPER in metabolic homeostasis and disease: molecular mechanisms, nutritional regulation, and therapeutic potential.Journal of translational medicine · 2025Review
- CTR-FAPI PET Enables Precision Management of Medullary Thyroid Carcinoma.Cancer discovery · 2025Article
- Epigenetics in thyroid cancer: a bibliometric analysis.Endocrine connections · 2024Article
- BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.Life metabolism · 2024Article
- Estrogen-related receptor alpha promotes thyroid tumor cell survival via a tumor subtype-specific regulation of target gene networks.Oncogene · 2024Article
- Forward Genetic Screens Identify Mechanisms of Resistance to Small-Molecule Lactate Dehydrogenase Inhibitors.ACS chemical biology · 2024Article
- Genomic alterations in thyroid cancer: biological and clinical insights.Nature reviews. Endocrinology · 2024Review
- Pathogenesis of cancers derived from thyroid follicular cells.Nature reviews. Cancer · 2023Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle 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-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant 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. SIGNIFICANCE: 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. See related article by Gopal et al., p. 1904. This article is highlighted in the In This Issue feature, p. 1749.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.