Journal News

JBC: Iron–sulfur cluster research offers new avenues for investigating disease

Sasha Mushegian
November 01, 2018

Many important proteins in the human body need iron-sulfur clusters, tiny structures made of iron and sulfur atoms, to function correctly. Researchers at the National Cancer Institute, the National Institutes of Health 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, published in the Journal of Biological Chemistry, provide clues about the biochemical causes of such conditions as 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.”

This stained histopathologic image shows clear-cell carcinoma of the kidney from a nephrectomy specimen. The cancer is named for its accumulation of lipid droplets.Courtesy of KGH/Wikimedia Commons 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.

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 eventually was 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 the NCI, is now examining the role of iron-sulfur cluster formation and aconitase function in cancers such as clear-cell carcinomas. Various cancers often are 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 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,” Crooks said, “… 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.”

Sasha Mushegian

Sasha Mushegian is a postdoctoral fellow at Georgetown University. Follow her on Twitter.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

In the future, lab mice will live in computer chips, not cages
Life in the Lab

In the future, lab mice will live in computer chips, not cages

July 11, 2020

As COVID-19 shuttered laboratories across the U.S., many researchers were forced to euthanize the animals they study. Lindsay Gray, a rodent surgeon in an animal research lab that faced this dilemma, argues here there is a safer, more effective way.

Proteomics reveals hallmarks of aging in brain stem cells
Journal News

Proteomics reveals hallmarks of aging in brain stem cells

July 09, 2020

Early in adulthood, the brain regenerates lost myelin effectively, but remyelination falters with age. Researchers seek to understand why — and what the change may mean for people with multiple sclerosis.

Ocean virus hijacks carbon-storing bacteria
Journal News

Ocean virus hijacks carbon-storing bacteria

July 07, 2020

A Journal of Biological Chemistry paper reports that these minuscule interactions could have ripple effects on global carbon dioxide levels.

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments
News

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments

July 04, 2020

Nearly 6 million Americans live with Alzheimer’s disease without solid treatment options.

Summer food science
Stroopwafels

Summer food science

July 02, 2020

For those of you bound for a summertime holiday weekend, we dug into recent research on the yummy foods you might serve at a socially distant picnic.

How lipid droplets stay in shape
Journal News

How lipid droplets stay in shape

June 30, 2020

Andrew Greenberg and colleagues discovered that the protein perilipin is involved in storage and hydrolysis of neutral lipids within these key structures in cells.