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.
Han X, Cheng H, Mancuso DJ, Gross RW. Caloric restriction results in phospholipid depletion, membrane remodeling, and triacylgycerol accumulation in murine myocardium. Biochemistry, 2004.
Funding from the National Institutes of Health and the Mildred and Clark Cox Fund supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Journal
Biochemistry