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Partially consumed are the specialized internal
membranes mitochondria use to generate energy-rich compounds for the
cell, making the mitochondrial strategy appear to create more problems
than it might solve. Nevertheless, the response appears to help
maintain healthy heart function throughout caloric restriction.
"It is likely that the changes in the membranes
make the mitochondria more energy efficient and serve as an adaptation
to nutritional deprivation in mammals," says Richard Gross, M.D., Ph.D.,
senior author and professor of medicine and director of the Division
of Bioorganic Chemistry and Molecular Pharmacology in the Department
of Medicine.
The findings, scheduled to be reported in an
upcoming issue of the journal Biochemistry and now available through
advance online publication, may have implications for human
cardiovascular health.
In their studies of mouse heart muscle, the
research team found levels of two members of a class of lipids (fatty
molecules) called phospholipids fell dramatically when food was
withheld. For one type of phospholipid, levels decreased by 20 percent
after only four hours of fasting and for the other, levels dropped a
remarkable 40 percent after twelve hours of fasting.
The changes in phospholipids occurred mainly in the
mitochondria, which are highly abundant in heart muscle cells and
account for most of the phospholipid content of the cells.
Mitochondria serve to break down many types of fats to produce the
high-energy cellular fuel ATP, which is essential for a multitude of
cellular processes, including the regular contraction of the heart
muscle.
"What we measured was a massive change in heart
lipid composition," Gross says. "In part, it confirms what science has
come to recognize--mitochondria are quite dynamic and change shape in
response to nutritional and hormonal cues. But we are the first to
report that mitochondria essentially remodel their own membranes, and
thereby their physical properties, by dynamically altering their use
of phospholipids."
A phospholipid decrease of the magnitude reported
is all the more surprising because phospholipids comprise essential
components of all cellular membranes and have previously been thought
to be preserved except in cases of extreme starvation.
The researchers' data also reveal that after
feeding resumes, the phospholipid levels in heart muscle cells rise
back to normal levels, indicating that mitochondria readily rebuild
their membranes.
During this recovery period, another class of lipid,
triglyceride, a common source of energy for many types of cells, peaks
high above its normal level in heart muscle cells. "The rise of
triglyceride isn't easily explained by nutritional conditions, because
after feeding resumes, the heart shouldn't need to increase its levels
of fats. It's as if the heart retains a memory of deprivation and
doesn't want to get caught unprepared again," Gross says.
The next step for the research team will be to
study the changes in shape and structure of mitochondria and to relate
these to changes to lipid metabolism.
The response by heart mitochondria might lend a
partial explanation to a pattern discerned in studies of ischemic
heart patients, who have restricted blood flow to the heart.
"While we have to be careful in drawing definitive
parallels between mouse lipid dynamics and human lipid dynamics, it is
interesting to note that the majority of sudden death in ischemic
heart patients occurs in the early morning hours when people have
typically had a long fast and are subject to a vast array of hormonal
influences during the sleep-wake cycle," Gross says. "The alterations
in heart muscle energy utilization during fasting may setup a
deleterious situation in the hearts of ischemic heart patients."
The research team uncovered the fluctuations in
cellular lipids through an innovative new technology they developed
called "shotgun lipidomics." As the name suggests, in comparison to
other techniques shotgun lipidomics has the speed and coverage of a
shotgun blast: From a simple one-step extraction of lipids in tissues,
the team can obtain in minutes highly accurate measurements of the
various cellular lipids, which previously have been notoriously
fragile, time-consuming to analyze and hard to quantify.
"Through the efforts of people in our division like
Xianlin Han, who has worked hard to perfect the technology, we have
been able to open up fresh avenues of investigation using shotgun
lipidomics," Gross says. |
