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

Gut microbiome shaped by dietary sphingolipids
Journal News

Gut microbiome shaped by dietary sphingolipids

September 22, 2020

A new tracing method described in the Journal of Lipid Research offers clues on how a macronutrient interacts with the microbes that live inside us.

From the journals: JBC
Journal News

From the journals: JBC

September 21, 2020

Proteases that fire up the flu. A sulfate pocket to take out MRSA. Proteins that prompt cancer protrusions. Read about recent papers on these topics and more.

AeroNabs promise powerful, inhalable protection against COVID-19
News

AeroNabs promise powerful, inhalable protection against COVID-19

September 20, 2020

As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease.

Keeping bone and muscle strong on the ISS
News

Keeping bone and muscle strong on the ISS

September 19, 2020

Researchers helped mice stay mighty with an experiment to counter the effects of microgravity. The gene treatment might also enhance muscle and bone health on Earth — and in humans.

Understanding the impact of Type 1 diabetes susceptibility genes
Research Spotlight

Understanding the impact of Type 1 diabetes susceptibility genes

September 17, 2020

Starting in eighth grade, a series of mentors who saw something special in Sharifa Love–Rutledge helped her stay on the path to being a researcher — and becoming a mentor to others.

Re-creating coagulation in a lab
Journal News

Re-creating coagulation in a lab

September 15, 2020

Threatened arthropods are in the crossfire of medical and conservation efforts, but new research could benefit horseshoe crabs and humans alike.