Iron-sulfur cluster research offers new avenues of investigating disease

May 30, 2018

Many important proteins in the human body need iron-sulfur clusters, tiny structures made of iron and sulfur atoms, in order to function correctly. Researchers at the National Cancer Institute (NCI), the National Institutes of Health (NIH) and the University of Kentucky have discovered that disruptions in the construction of iron-sulfur clusters can lead to the buildup of fat droplets in certain cells. These findings, which will be published in the May 25 issue of the Journal of Biological Chemistry, provide clues about the biochemical causes of conditions like nonalcoholic fatty liver disease and clear cell renal carcinoma.

"Iron-sulfur clusters are delicate and susceptible to damage within the cell," said Daniel Crooks, the postdoctoral fellow who led the new study. "For this reason, the cells in our body are constantly building new iron-sulfur clusters."

Crooks began studying the enzymes that build iron-sulfur clusters during his graduate studies in Tracey Rouault's lab at the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH. Mutations in one of these enzymes can cause ISCU myopathy, a hereditary condition in which patients, despite seeming strong and healthy, cannot exercise for more than a short time without feeling pain and weakness.

Therefore, it was clear to Crooks that lifelong deficiency of iron-sulfur clusters caused profound changes in how cells processed energy. But he wondered exactly what happened in a cell in the first moments after something went wrong with iron-sulfur cluster production. Which of the many proteins that need iron-sulfur clusters were affected first, and what effect did this have on cell metabolism?

Crooks developed experimental methods to abruptly stop iron-sulfur clusters from being manufactured in cells and to monitor what happens to how these cells process glucose. Ordinarily, over a series of metabolic steps, cells would convert glucose into energy. But without iron-sulfur clusters, an enzyme called aconitase that carries out one of the steps in this process doesn't work. As a result, the cells quickly accumulated an intermediate metabolic product called citrate, which was eventually converted into droplets of fat.

Over-accumulation of fats in tissues where they're not normally found is a hallmark of numerous diseases, including nonalcoholic fatty liver disease, a risk factor for cirrhosis and liver cancer. These findings suggest that this state could be caused by failures of iron-sulfur cluster production, for example due to cellular stressors or toxin exposure.

"We're hoping that the people who are working so hard on nonalcoholic fatty liver disease will find our paper helpful to their research," Rouault said.

Crooks, working in the laboratory of surgeon and scientist W. Marston Linehan at NCI, is now examining the role of iron-sulfur cluster formation and aconitase function in cancers, for example clear cell carcinomas. Various cancers are often characterized by excessive fat accumulation in cells. In fact, this accumulation of lipid droplets is where clear cell carcinomas get their name: when a slice of a such a tumor is fixed on a slide and its proteins are stained, the large areas of lipid accumulation in the cells look transparent.

"We really want to look at the beginnings of cancer...to understand whether the lipids were formed from glucose or other fuels and whether the lipids are important for pathogenesis, or whether they're just bystanders that form in response to metabolic reprogramming which is likely to include disruption of iron sulfur protein activities," Crooks said.
-end-
About the Journal of Biological Chemistry

JBC is a weekly peer-reviewed scientific journal that publishes research "motivated by biology, enabled by chemistry" across all areas of biochemistry and molecular biology. The read the latest research in JBC, visit http://www.jbc.org/.

About the American Society for Biochemistry and Molecular Biology

The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society's student members attend undergraduate or graduate institutions. For more information about ASBMB, visit http://www.asbmb.org.

American Society for Biochemistry and Molecular Biology

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.