For a month in 1962, India and China fought a war in the Himalayan highlands. In the high-altitude, frigid conditions, physical endurance was at least as much of a threat to the soldiers on each side as the opposing army. Perhaps one reason that China won is that many of the soldiers on their side were native to the region and well conditioned to handle the cold and low-oxygen environment. If you could look inside the cells of those soldiers’ lungs and other tissues, perhaps these soldiers had an arsenal of microscopic secret weapons that made their physical endurance possible.
Those secret weapons are mitochondria, according to Liming Pei, PhD, and Douglas Wallace, PhD, of the Center for Mitochondrial and Epigenomic Medicine (CMEM) at Children’s Hospital of Philadelphia and Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. In the early 1990s, Dr. Wallace became interested in studying whether mitochondria — the organelles inside cells that generate 90 percent of the body’s energy — were responsible for different populations’ abilities to withstand high-altitude conditions. He and several U.S. colleagues partnered with the Third Military Medical University in China to analyze the DNA within the mitochondria (mitochondrial DNA), comparing samples from people native to Tibet in the Himalayas with those from lowland Han Chinese populations.
They found a variant in the mitochondrial DNA that was frequent among Tibetans and rare in Han Chinese — a tantalizing clue that this variant was under positive selection in the highlands, and that mitochondrial function could make a difference in performance in that setting, perhaps even tipping the balance in a battle.
Dr. Pei and Dr. Wallace are now returning to the study of mitochondrial function in a military setting with a grant from the U.S. Army. Their powerful collaboration builds on the strength of both scientists’ labs. Dr. Pei specializes in the study of how mitochondrial genes are transcribed and function within the cell, and Dr. Wallace is an expert in mitochondrial genetics and mitochondrial diseases and a founder of the field of mitochondrial medicine.
“Mitochondrial disease affects many parts of the body, and the parts most affected are the brain, heart, and skeletal muscles, because those parts of the body have a lot of mitochondria and use a lot of energy,” Dr. Pei said. “For proof of principle, we are focusing on the heart because you can evaluate cardiac function fairly well in animal models.”
Their project could help improve mitochondrial function for the benefit of U.S. service members and their families, veterans, and civilians, including children and adults with mitochondrial diseases. Mitochondrial DNA is distinct from the DNA in the cell’s nucleus. Mitochondrial diseases are inherited conditions caused by a number of different mutations in mitochondrial DNA and in nuclear genes that are involved in the functions of mitochondria.
Over the last few years, Dr. Pei identified a family of transcription factor proteins to be essential for the production of mitochondria and of proteins involved in energy generation in neurons (ERR gamma) and heart cells (ERR alpha and ERR gamma).
“Our idea was that, if you increase the level of these particular proteins, that would cause the cell to make more mitochondria, and that might in fact then increase the energy output of the cell and make the cell healthier,” Dr. Pei said.
While other efforts to develop therapies for mitochondrial diseases take a precision approach, Drs. Wallace and Pei aim to power up mitochondria broadly, regardless of the underlying mutation that might cause dysfunction or disease. This is a plausible option because patients with mitochondrial disease often have a combination of some damaged mitochondria and some healthy ones. If their method increases the number of healthy mitochondria or increases healthy proteins to aid the function of unhealthy mitochondria, the net effect could be improvements in energy production.
Their study uses three different preclinical models of cardiomyopathy due to mitochondrial dysfunction. Two are mouse models with different mitochondrial mutations that result in cardiomyopathy. The third is induced pluripotent stem cells derived from a large mitochondrial cardiomyopathy lineage that their collaborator, Xilma Ortiz-Gonzalez, MD, PhD, of the division of Pediatric Neurology at CHOP, has successfully grown into human cardiomyocytes (heart cells).
They will test gene therapy approaches to increase the expression of the ERR alpha or ERR gamma transcription factor and pharmacologic interventions to increase that protein’s activity. In their proof-of-principle approach, they hope to show that increasing these proteins boosts the number and function of mitochondria therapeutically for cell and animal models, and potentially to show the safety of the approach in animals.
If the principle proves successful, it opens the possibility that this type of method for boosting mitochondrial function could benefit many people with mitochondrial dysfunction, since mitochondrial defects are being associated with a broad range of common diseases such as diabetes, obesity, and neurological diseases. For military personnel and veterans, these approaches might ameliorate some of the negative effects of conflict toxicity such as exposure to Agent Orange and conditions such as Gulf War syndrome. Improving mitochondrial function could benefit people who are not sick — such as soldiers fighting in the mountains.
“It would be amazing, for instance, if we could use ERR alpha/gamma as a preventative therapy for high altitude or even just increase the mitochondrial level of people, making them more resistant to stress, for instance, able to exercise longer, or able to recover from toxins,” Dr. Wallace said. “There are many potential applications long down the road.”
Produced by The Children’s Hospital of Philadelphia Research Institute.
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