ArticleScience signaling2021
Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.
Open access · greenAbstract read
In one paragraph
Article in Science signaling, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed, 1 pooled it
10.6field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.
- Association between fumarate hydratase variant subtypes and the risk of HLRCC-associated renal cell carcinoma: systematic review and meta-analysis.Human genomics · 2025Pooled it
- Cancer-derived lactic acid as a potential upstream contributor to tumor hypoxia.Communications biology · 2026Review
- Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).Cell communication and signaling : CCS · 2026Review
- Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Molecular regulatory network of glycolytic reprogramming in hepatocellular carcinoma and its clinical implications.Biological procedures online · 2025Review
- Differential Efficacy of Bevacizumab and Erlotinib in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase-Deficient Renal Cell Carcinoma.Molecular cancer therapeutics · 2025Article
- Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.Science advances · 2025Review
- Targeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping.Molecular therapy. Nucleic acids · 2025Article
- Targeting metabolic and epigenetic reprogramming in metastatic fumarate hydratase-deficient renal cell carcinoma.Clinical & experimental metastasis · 2025Review
- Oxidative and Glycolytic Metabolism: Their Reciprocal Regulation and Dysregulation in Cancer.Cells · 2025Review
- Organelle-oriented nanomedicines in tumor therapy: Targeting, escaping, or collaborating?Bioactive materials · 2025Review
- Targeting NAD+ Metabolism Vulnerability in FH-Deficient Hereditary Leiomyomatosis and Renal Cell Carcinoma with the Novel NAMPT Inhibitor OT-82.Molecular cancer therapeutics · 2025Article
- Integrated multi-omics analysis reveals a glycolytic signature that predicts pan-cancer immune checkpoint inhibitor response and LDHA as a combinatorial target in fumarate hydratase-deficient renal cell carcinoma.Frontiers in immunology · 2025Article
- Tumor innervation and mitochondrial transfer in the cancer pathogenesis: perspectives on genitourinary malignancies.Frontiers in oncology · 2025Review
- The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities.Neoplasia (New York, N.Y.) · 2024Review
- Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance.International journal of molecular sciences · 2024Review
- Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma.NAR cancer · 2024Article
- MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.JCI insight · 2023Article
- Cryptic splice mutation in the fumarate hydratase gene in patients with clinical manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer.Human molecular genetics · 2023Article
- Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism.British journal of cancer · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
27 authors at 6 institutions in 1 country.
Daniel R CrooksUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0002-9198-4089
Nunziata MaioMolecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.ORCID 0000-0002-6225-6058
Martin LangUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0002-0242-6713
Christopher J RickettsUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0003-4814-7207
Cathy D VockeUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0002-9256-7607
Sandeep GurramUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0002-6405-9269
Sevilay TuranSequencing Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA.
Yun-Young KimUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0002-6592-9545
G Mariah CawthonUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Ferri SohelianElectron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
Natalia De ValElectron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.ORCID 0000-0002-1506-2023
Ruth M PfeifferBiostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.ORCID 0000-0001-7791-2698
Parthav JailwalaCCR Collaborative Bioinformatics Resource (CCBR), Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
Mayank TandonCCR Collaborative Bioinformatics Resource (CCBR), Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.ORCID 0000-0002-1675-5040
Bao TranSequencing Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21701, USA.
Teresa W-M FanCenter for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.ORCID 0000-0002-7292-8938
Andrew N LaneCenter for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Thomas RiedGenetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0002-0767-6009
Darawalee WangsaGenetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Ashkan A MalayeriRadiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Maria J MerinoGenitourinary Pathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
Youfeng YangUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Jordan L MeierEpigenetics and Metabolism Section, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.ORCID 0000-0002-0537-7101
Mark W BallUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0003-1780-2627
Tracey A RouaultMolecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.ORCID 0000-0003-0062-0245
Ramaprasad SrinivasanUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.ORCID 0000-0001-6392-3169
W Marston LinehanUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. wml@nih.gov.ORCID 0000-0001-7983-3109
National Cancer Institute · USLeidos (United States) · USEunice Kennedy Shriver National Institute of Child Health and Human Development · USMarkey Cancer Center · USFrederick National Laboratory for Cancer Research · USNational Institutes of Health Clinical Center · US
Funding
Methods for Epidemiology StudiesZIACP010181 · NCI · DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS · PI ALBERT, PAUL · 2009 to 2025
$34.8MCCR Collaborative Bioinformatics ResourceZICBC011532 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI MALIK, MARIAM · 2013 to 2025
$33.7MMolecular Therapeutics of Kidney Cancer: VHL Gene and Fumarate Hydratase GeneZIABC011038 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI LINEHAN, WILLIAM MARSTON · 2009 to 2025
$29.8MRegulation Of Intracellular Iron MetabolismZIAHD001602 · NICHD · EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT · PI ROUAULT, TRACEY A. · 2009 to 2025
$21.8MTargeting Cancer Through Modifications and MetabolismZIABC011488 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI MEIER, JORDAN L · 2013 to 2025
$21.3MClinical Studies of the Molecular Genetic Basis of Kidney CancerZIABC011028 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI LINEHAN, WILLIAM MARSTON · 2009 to 2025
$17.9MClinical Nursing and Data Management CoreZIDBC011089 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI LINEHAN, WILLIAM MARSTON · 2009 to 2025
$17.4MTissue ProcessingSequencing FacilityZICBC011044 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI VOCKE, CATHY D · 2009 to 2025
$13.5MTargeting Genetic and Metabolic Alterations in Distinct Subtypes of RCCZIABC011648 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI SRINIVASAN, RAMAPRASAD · 2015 to 2025
$12.2MMetabolomics CoreZICBC011932 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI CROOKS, DANIEL · 2020 to 2025
$11.6MTUMOR SUPPRESSOR GENES IN GENITOURINARY MALIGNANCYZ01SC006659 · SC · CLINICAL SCIENCES · PI LINEHAN, WILLIAM MARSTON · 1996 to 2007
$4.0MMolecular Therapeutics of Kidney Cancer: VHL Gene and Fumarate Hydratase GeneZ01BC011038 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI LINEHAN, WILLIAM MARSTON · 2008 to 2008
$1.4MIntramural NIH HHS Z01 BC011028Intramural NIH HHS Z01 BC011038Intramural NIH HHS Z01 BC011044Intramural NIH HHS Z01 BC011089Intramural NIH HHS Z01 SC006659
Abstract
Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
Indexed as
Citric Acid CycleDNA DamageAdultAgedCarcinoma, Renal CellDNA, MitochondrialDNA RepairDNA ReplicationFemaleFumarate HydrataseGene Expression ProfilingHumansKidney NeoplasmsLeiomyomatosisMaleMiddle AgedDNA, MitochondrialFumarate Hydratase
Identifiers
What OpenQuestion holds
Textmetadata
LicenceTDM
Read underepoch 390
Registered trials
None linked
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.