| |
News from Newswise Mar. 23, 2007
Metabolic Strategy of Stressed
Cell
Newswise — 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.
A report on this work appears in the March issue of Chemistry &
Biology.
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 (
http://www.stjude.org/media/0,2561,453_5715_21400,00.html
).
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.).
This work was supported in part by the National Institutes of Health,
a Cancer Center (CORE) Grant and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized
for its pioneering work in finding cures and saving children with
cancer and other catastrophic diseases. Founded by late entertainer
Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its
discoveries with scientific and medical communities around the
world. No family ever pays for treatments not covered by insurance,
and families without insurance are never asked to pay. St. Jude is
financially supported by ALSAC, its fundraising organization. For
more information, please visit
http://www.stjude.org .
http://www.newswise.com/articles/view/528398/?sc=rsmn
<----back |
|