Investigators at St. Jude Children's Research Hospital have mapped out many of the dynamic genetic and biochemical changes that make up a cell's response to a shortage of a molecule called Coenzyme A (CoA), a key player in metabolism. The results provide the most detailed look ever obtained of the complex metabolic changes in a cell triggered by a potentially fatal stress.
Metabolism is the sum of all biochemical reactions involved in maintaining the health of the cell, including breaking down and synthesizing various molecules to produce energy and build substances the cell needs to operate normally. CoA plays key roles in the cell's metabolism by participating in biochemical reactions in specific areas throughout the cell.
The St. Jude study is a significant contribution to the growing field of metabolomics--the study of the molecules involved in metabolism. Coupled with genetic studies of the cell, metabolomics is giving scientists a more detailed picture of how the body maintains its health in both normal environments and during times of stress, such as starvation or disease.
The researchers studied the response to decreased CoA in a mouse model by blocking CoA production with hopantenate (HoPan). HoPan is a chemical that interferes with pantothenate kinase (PanK), the enzyme that triggers the first step of CoA production. Following the shutdown of CoA production, the cells quickly recycled CoA from other jobs so it could concentrate all its efforts on a single task: extracting life-supporting energy from nutrients in the mitochondria. Mitochondria are the powerhouses of the cell, so-called because these bags of enzymes host a series of complex biochemical pathways that produce the energy-rich molecule ATP--the cell's "currency" with which it "buys" chemical reactions that consume energy.
"The cell's response to reduced CoA levels is like the driver of a car that is low on gas," said Charles Rock, Ph.D., a member of the St. Jude Infectious Diseases department and co-author of the paper. "The driver might try to save what little gas is left by turning off the air conditioner and driving slower," he said. "Likewise, by shutting down or limiting the other biochemical pathways that use CoA, the cell can concentrate it in the mitochondria where it's needed most."
"The metabolic changes we observed freed up the CoA to make ATP," said Suzanne Jackowski, Ph.D., a member of the St. Jude Infectious Diseases department and the paper's senior author. "Our study provides the first detailed look at how the cell shifts genetic gears to respond to a significant change in its ability to carry on its daily metabolic chores."
The St. Jude study also showed that PanK controls the concentration of CoA in the cell depending on how much is needed and where it is needed. Previous studies at St. Jude showed that four different forms of PanK exist in different places in the cell and each one can be inhibited by rising levels of CoA. This allows the cell to increase or decrease CoA levels in specific locations, depending on the amount of CoA needed.
These findings not only give researchers a detailed look at how the cell responds to a significant reduction in the concentration of a critical molecule. The alterations in the activity of certain genes and enzymes also serve as a model for the milder disruption of CoA levels that may underlie a brain disorder called pantothenate-kinase-associated neurodegeneration (PKAN). PKAN is a hereditary disorder caused by mutations in PanK that may lead to a deficiency of CoA in brain mitochondria. Previously, this group of St. Jude researchers showed how specific mutations in one form of PanK disable this enzyme, which in turn would reduce CoA production and cause PKAN .
In the present study, the St. Jude team showed that low levels of CoA trigger the activation of genes that block other biochemical pathways that ordinarily use this molecule. Instead, the cell shifts most of the available CoA activity to producing glucose from the liver. Other organs then break down glucose into a molecule called pyruvate inside structures called mitochondria. In the mitochondria, CoA molecules perform another job: feeding pyruvate into a complex series of chemical reactions that produces molecules of ATP.
"Our results identify the re-arrangements that the cell's metabolism undergoes in order to ensure that the liver keeps CoA levels high enough to produce glucose and the cells of the body maintain enough free CoA for the mitochondria to keep producing ATP," said Yong-Mei Zhang, Ph.D., of the St. Jude Infectious Diseases department and first author of the report.
The investigators demonstrated many of the metabolic changes caused by a shortage of CoA by treating mice with HoPan. The resulting decrease in CoA triggered severe hypoglycemia--a low level of glucose in the blood. Prior to the hypoglycemia, the liver cells adjusted their metabolism in an effort to maintain the glucose output. This study identified several key steps, including a substantial increase in the amount of enzymes that free CoA from molecules called acyl groups, as well as increases in the amount of acylcarnitine, a molecule that grabs those acyl groups, ensuring that CoA remains free and available for energy production.
Other authors of this paper include Shigeru Chohnan (St. Jude), Kristopher G. Virga and Richard E. Lee (University of Tennessee Health Science Center, Memphis, Tenn.); Robert D. Stevens, Olga R. Ilkayeva, Brett R. Wenner, James R. Bain and Christopher B. Newgard (Duke University Medical Center, Durham, N.C.).
A report on this work appears in the March issue of "Chemistry and Biology. "
This work was supported in part by the National Institutes of Health, a Cancer Center (CORE) Grant and ALSAC.
Materials provided by St. Jude Children's Research Hospital. Note: Content may be edited for style and length.
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