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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 (see below).
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. |
