The body’s fight or flight response is all too familiar to many of us, even if we’ve never been confronted with a life or death situation before. As college students, we may have to give a presentation in front of a large class, drink several cups of coffee in order to finish an essay or even just ask our romantic interest out on a date — situations which can induce a variety of responses from the human cardiovascular system. These symptoms include stomach “butterflies” and an accelerated heart rate. However, some people may experience these symptoms without any sort of external stimulus. Medical and psychological conditions, such as heart disease and schizophrenia, can cause the heart to race uncontrollably and unpredictably, and in some cases it can be deadly.
By studying mice hearts, a team of Hopkins researchers led by Yuejin Wu and Mark Anderson has identified the cell structure that may be responsible for such a response in humans. Cells of the heart often need to work continuously and at maximum efficiency and thus contain a high density of mitochondria. A highly selective ion channel, the mitochondrial calcium uniporter (MCU), resides on the mitochondrial inner membrane and assists in the uptake of large amounts of calcium ions. This increases the electrochemical gradient across the inner membrane, which drives the production of energy in the form of adenosine triphosphate (ATP).
In order to examine the MCU’s role in regulating mitochondrial activity, the researchers inhibited the function of the ion channel in mice in several ways. First, they injected into heart cells a compound that blocks the ion channel. They then exposed both the altered cells and normal cells to the stimulant isoproterenol. While both kinds of cells maintained a normal beating rate in the absence of isoproterenol, the unaltered cells beat much faster than the altered ones after the stimulant was added. The beating rate of the altered cells was increased with the addition of ATP, suggesting that the proper functioning of MCUs is crucial to the production of normal and sufficient levels of ATP.
Next, the researchers made modifications to the whole heart by introducing a virus that contained an MCU-blocking gene. By interacting with the heart cells, the virus was able to insert this gene into the cells’ DNA. The altered organ showed a similar decreased response to isoproterenol compared to that of a normal healthy mouse heart.
Finally, the researchers introduced the MCU blocking gene natively to the DNA and bred mice with the mutation. They then monitored the animals’ heart rates through normal activity and observed that they remained relatively constant even during exercise or moments of danger.
The research shows that effects of an increased heart rate, which typically manifest on the tissue and organismal levels, as in schizophrenia, may arise from something as small as individual structures within a cell. However, current medications for high heart rates tend to focus primarily on the observable symptoms of this increase. As a result they can slow heart rate uniformly, meaning that the resting heart rate is also depressed. This can produce undesirable side effects including fatigue and nausea.
With further research on MCUs in human heart cells, pharmaceutical companies may be able to specifically target these ion channels in order to treat high heart rates. To many in the scientific community, the revelation that mitochondria are crucial to the proper functioning of hardworking heart cells is no surprise. Now the new challenge lies in figuring out the specific mechanism by which MCUs affect the production of ATP and if altering them on a smaller scale will actually make a difference for the organism as a whole.
