Skip to main content
NIH Intramural Research Program, Our Research Changes Lives

Navigation controls

  • Search
  • Menu

Social follow links

  • Podcast
  • Instagram
  • Twitter
  • YouTube
  • LinkedIn

Main navigation

  • About Us
    • What Is the IRP?
    • History
    • Honors
      • Nobel Prize
      • Lasker Award
      • Breakthrough Prize
      • Presidential Early Career Award for Scientists and Engineers (PECASE)
      • Presidential Medal of Freedom
      • National Medal of Science
      • Searle Scholars
      • The National Academy of Sciences
      • The National Academy of Medicine
      • The National Academy of Engineering
      • The American Academy of Arts and Sciences
      • National Medal of Technology & Innovation
      • Samuel J. Heyman Service to America Medals
      • Crafoord Prize
      • Fellows of the Royal Society
      • Canada Gairdner Awards
    • Organization & Leadership
    • Our Programs
      • NCI
      • NEI
      • NHGRI
      • NHLBI
      • NIA
      • NIAAA
      • NIAID
      • NIAMS
      • NIBIB
      • NICHD
      • NIDA
      • NIDCD
      • NIDCR
      • NIDDK
      • NIEHS
      • NIMH
      • NIMHD
      • NINDS
      • NINR
      • NLM
      • CC
      • NCATS
      • NCCIH
    • Research Campus Locations
    • Contact Information
  • Our Research
    • Scientific Focus Areas
      • Biomedical Engineering & Biophysics
      • Cancer Biology
      • Cell Biology
      • Chemical Biology
      • Chromosome Biology
      • Clinical Research
      • Computational Biology
      • Developmental Biology
      • Epidemiology
      • Genetics & Genomics
      • Health Disparities
      • Immunology
      • Microbiology & Infectious Diseases
      • Molecular Biology & Biochemistry
      • Molecular Pharmacology
      • Neuroscience
      • RNA Biology
      • Social & Behavioral Sciences
      • Stem Cell Biology
      • Structural Biology
      • Systems Biology
      • Virology
    • Principal Investigators
      • View by Investigator Name
      • View by Scientific Focus Area
    • Accomplishments
      • View All Accomplishments by Date
      • View All Health Topics
      • The Body
      • Health & Wellness
      • Conditions & Diseases
      • Procedures
    • Accelerating Science
      • Investing in Cutting-Edge Animal Models
      • Creating Cell-Based Therapies
      • Advancing Computational and Structural Biology
      • Combating Drug Resistance
      • Developing Novel Imaging Techniques
      • Charting the Pathways of Inflammation
      • Zooming in on the Microbiome
      • Uncovering New Opportunities for Natural Products
      • Stimulating Neuroscience Research
      • Pursuing Precision Medicine
      • Unlocking the Potential of RNA Biology and Therapeutics
      • Producing Novel Vaccines
    • Research in Action
      • View All Stories
      • Too Much of a Good Thing
      • Turning Face Perception on Its Head
      • Safeguarding a Second Chance at Life
      • A Biological Betrayal
    • Trans-IRP Research Resources
      • Supercomputing
    • IRP Review Process
    • Commercializing Inventions
  • NIH Clinical Center
    • Clinical Center Facilities
    • Advancing Translational Science
    • Clinical Trials
      • Get Involved with Clinical Research
      • Physician Resources
  • News & Events
    • In the News
    • I am Intramural Blog
    • Speaking of Science Podcast
    • SciBites Video Shorts
    • The NIH Catalyst Newsletter
    • Events
  • Careers
    • Faculty-Level Scientific Careers
    • Trans-NIH Scientific Recruitments
      • Stadtman Tenure-Track Investigators
        • Science, the Stadtman Way
        • Earl Stadtman Investigator Frequently Asked Questions
      • Lasker Clinical Research Scholars
      • Independent Research Scholar
    • Scientific & Clinical Careers
    • Administrative Careers
  • Research Training
    • Program Information
    • Training Opportunities
    • NIH Work/Life Resources
The NIH Catalyst: A Publication About NIH Intramural Research

National Institutes of Health • Office of the Director | Volume 29 Issue 2 • March–April 2021

Research Briefs: Kidney Disease

New Insights into What Fuels an Aggressive Form of Kidney Disease

ADAPTED FROM AN NCI-CCR NEWS ARTICLE

cells in black and white

CREDIT: DANIEL R. CROOKS ET AL., NCI

The ultrastructure of damaged mitochondria in a tumor from a patient with kidney cancer associated with hereditary leiomyomatosis and renal cell carcinoma.

Scientists in the National Cancer Institute’s Center for Cancer Research have uncovered an important mechanism that fuels an aggressive form of kidney disease. The results, published recently in Science Signaling, show how deficiency of an important enzyme severely impairs cells’ ability to repair and maintain healthy mitochondrial DNA. The resulting mitochondrial DNA mutations causes the cells to become more aggressive. [Sci Signal 14 (issue 664):eabc4436, 2021;DOI:10.1126/scisignal.abc4436]

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is considered one of the most aggressive forms of kidney cancer. A key characteristic of this cancer is the lack of an enzyme called fumarate hydratase (FH).

W. Marston Linehan, chief of NCI’s Urologic Oncology Branch, has studied HLRCC in the past and found that a FH deficiency is associated with a shift in how HLRCC cells process energy. Whereas healthy cells typically use mitochondria to convert oxygen into energy, cancerous HLRCC cells tend to rely on a different mechanism—called aerobic glycolysis—for energy production that doesn’t require oxygen. However, the mechanism by which FH deficiency causes cancer cells to shift to this alternative way of producing energy, which is associated with more aggressive cancer growth and spread, remains unknown.

Linehan and his colleagues, including Dan Crooks, Nunziata Maio, Jordan Meier, Mark Ball, Ramaprasad Srinivasan, and Tracey Rouault, sought to better understand the mechanism behind this shift. They collected and analyzed 25 tumor samples from patients with HLRCC and found that, without sufficient FH, which catalyzes the hydration of fumarate to malate, a harmful amount of fumarate, which is an oncometabolite, accumulates in the cells. Oncometabolites are conventional metabolites that, when accumulated abnormally, can trigger cancer.

Genetic analysis revealed that this accumulation caused damage to important mitochondrially encoded genes, including POLG, that are responsible for replicating and maintaining healthy DNA. The overall number of mitochondrial genes, including genes encoding the components of the electron-transport chain, in the cells were greatly reduced and/or mutated; resulting in impairment of oxidative phosphorylation and a shift to aerobic glycolysis. The researchers attempted to reverse this phenomenon by adding more FH to the cells but found that the damage was irreversible.

“These findings provide the foundation for the development of targeted therapies for patients with fumarate hydratase–deficient renal cancers characterized by a shift to aerobic glycolysis,” said Linehan. “We are currently working with Ram Srinivasan and others to develop therapies that target the pathways that are promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent cancer.”


This article is adapted from one that appeared on the NCI-CCR news website: https://ccr.cancer.gov/news/article/new-insights-into-what-fuels-an-aggressive-form-of-kidney-disease.

This page was last updated on Tuesday, February 15, 2022

  • Issue Overview
  • Features
    • The 1918 Flu and COVID-19: A Tale of Two Pandemics
    • Introducing NIH’s Newest Lasker Scholars
    • Stadtman Investigators Pursuing Their Passion for Science
    • Fueling the Next Genomic Revolution
    • COVID-19 Timeline at NIH (JANUARY-FEBRUARY 2021)
  • Departments
    • From the Deputy Director for Intramural Research
    • From the Annals of NIH History
    • From the Annals of NIH History: Lefkowitz
    • Research Briefs
    • Research Briefs: Maternal Morbidity and Mortality
    • Research Briefs: Kidney Disease
    • The Training Page
    • Announcements: Kudos to Dan Kastner
    • Photographic Moment
    • Announcements
  • Issue Contents
  • Download this issue as a PDF

Catalyst menu

  • Current Issue
  • Previous Issues
  • About The NIH Catalyst
  • Contact The NIH Catalyst
  • Share Your Story
  • NIH Abbreviations

Catalyst links

  • Follow The NIH Catalyst

Subscribe Today!

Subscribe to The NIH Catalyst Newsletter and receive email updates.

Subscribe

Get IRP Updates

Subscribe

  • Email
  • Print
  • Share Twitter Facebook LinkedIn

Main navigation

  • About Us
    • What Is the IRP?
    • History
    • Honors
    • Organization & Leadership
    • Our Programs
    • Research Campus Locations
    • Contact Information
  • Our Research
    • Scientific Focus Areas
    • Principal Investigators
    • Accomplishments
    • Accelerating Science
    • Research in Action
    • Trans-IRP Research Resources
    • IRP Review Process
    • Commercializing Inventions
  • NIH Clinical Center
    • Clinical Center Facilities
    • Advancing Translational Science
    • Clinical Trials
  • News & Events
    • In the News
    • I am Intramural Blog
    • Speaking of Science Podcast
    • SciBites Video Shorts
    • The NIH Catalyst Newsletter
    • Events
  • Careers
    • Faculty-Level Scientific Careers
    • Trans-NIH Scientific Recruitments
    • Scientific & Clinical Careers
    • Administrative Careers
  • Research Training
    • Program Information
    • Training Opportunities
    • NIH Work/Life Resources
  • Department of Health and Human Services
  • National Institutes of Health
  • USA.gov

Footer

  • Home
  • Contact Us
  • IRP Brand Materials
  • HHS Vulnerability Disclosure
  • Web Policies & Notices
  • Site Map
  • Search