The heart needs energy to pump blood. Thus, the defects of energy production in the heart muscles lead to various heart diseases.
Scientists at Texas A&M AgriLife have now discovered a new link between calcium, heart energy production, and cardiolipin, a type of fat. The discovery helps explain heart defects in Barth syndrome, a rare genetic disorder.
The study, published in Proceedings of the National Academy of Sciences on June 29, was led by Vishal M. Gohil, Ph.D., Department of Biochemistry and Biophysics, Texas A&M College of Agriculture and Life Sciences. The other co-authors were from the University of Texas at San Antonio Health Sciences Center and Massachusetts General Hospital in Boston. Research funding for this study comes from the Welch Foundation and the National Institutes of Health.
HEART DEFECTS IN BARTH’S SYNDROME
Barth syndrome is a rare genetic disorder that occurs almost exclusively in boys. The children concerned suffer from heart and muscle weakness from early childhood. In this debilitating disease, patients find it difficult to do routine activities such as walking and running. Often their hearts are weak and enlarged.
People with Barth syndrome have a genetic defect that interferes with their body’s ability to make cardiolipin. As the name suggests, cardiolipin is present in large amounts in the muscles of the heart. Cardiolipin belongs to a class of molecules called lipids.
In muscle cells, cardiolipin is found in the mitochondria, which are known as the âpowerhouseâ of the cell because they produce biological energy from the food we eat. Cardiolipin and other lipids form the membrane “skin” of mitochondria, but cardiolipin appears to be a particularly crucial component. A shortage of cardiolipin undermines the ability of mitochondria to produce energy in the form of adenosine triphosphate, ATP.
A LINK BETWEEN CARDIOLIPINE, ENERGY AND CALCIUM
When cells need a burst of energy, they use calcium as a signal to prompt the mitochondria to increase energy production. Calcium ions enter the mitochondria through a special channel in the mitochondrial membrane. Since the calcium channel is present in the same membrane as cardiolipin and other lipids, Gohil and his team wondered what effect lipids have on the channel.
âWe knew this channel is in the mitochondrial membrane, so we asked if membrane lipids could impact how this channel works? Said Gohil.
BAKERY YEAST HELPS STUDY ENERGY PRODUCTION IN BARTH SYNDROME
Gohil’s lab had already found a way to make yeast mitochondria deficient in various lipids, including cardiolipin. Yeasts have mitochondria that are very similar to humans in many ways, but they lack the calcium channel.
Sagnika Ghosh, lead author of the study and a graduate student of Gohil’s lab, genetically engineered baker’s yeast mitochondria to include the human calcium channel. She then looked at what happens to calcium transport when the lipid composition of the membrane changes.
âWe found that the calcium channel was not stable in a mitochondrial membrane with a low amount of cardiolipin, like the amount seen in patients with Barth syndrome,â Gohil said.
CONFIRMATION IN PATIENT SAMPLES
Next, the team acquired cells and heart tissue samples from patients with Barth syndrome. The team confirmed that what they saw in their yeast experiments is also happening in patient samples. Because the mitochondrial calcium channels were unstable, the mitochondria of patients with Barth syndrome were much less permeable to calcium than those of healthy cells.
So when a patient’s cells need a burst of energy, sending a calcium signal to the mitochondria may not increase energy production like it would in a healthy cell.
“Starting from a fundamental scientific question, our work led to a discovery related to human health,” Gohil said. “In this genetic disease, a lack of calcium absorption could in turn affect energy production. What we observed in yeast was also true in human cells.”
Gohil’s lab recently obtained research funding from the Barth Syndrome Foundation to further investigate these findings. The team will use cells from patients with Barth syndrome to describe how calcium signaling contributes to symptoms of the disease.