by Jackie Swift
Inside almost every cell in our bodies live little powerhouses known as mitochondria. These tiny organelles, with their own genome, primarily produce adenosine triphosphate (ATP), the fuel on which your cells depend in order to function. If something goes wrong in the chain of mitochondrial electron transport components that ultimately produce ATP, disease results.
“ATP production is the only system in the body that is under dual genetic control,” says Joeva J. Barrow, Nutritional Sciences at Cornell University. “Your nuclear genes and your mitochondrial genes work together to make the system functional. Any defect in either genome leads to disease because if you can’t produce enough ATP, then you don’t have enough energy in your body, and your cells begin to die. Typically tissues that are very energetic and require a lot of ATP, like the brain, heart, and muscles, are most susceptible.”
Mitochondrial Disorders, What Are They
There is no cure for mitochondrial disorders, which are hard to diagnose and impossible to treat. They result in complex diseases that are hardly household names, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leber’s hereditary optic neuropathy (LHON), yet they are more common than most people realize. One in 4,500 people suffer from a mitochondrial disease, and one in 200 show no symptoms but carry a mitochondrial mutation potentially able to trigger disease later in life or when passed on to the next generation. These asymptomatic carriers are all women, since mitochondria are maternally inherited.
To understand the processes that cause mitochondrial disease, as well as potential treatments, the Barrow lab depends on unbiased, high-throughput screening mechanisms, such as small molecule chemical targeting and genome-wide CRISPR-Cas9 gene ablations. “Our goal is to identify any genes or proteins that may be linked to mitochondrial bioenergetics, then significantly leverage them to see if we can push them toward therapy,” Barrow says.
Studying the Genetics and Biochemistry Underlying Mitochondrial Disorders
The researchers use a combination of cell and mouse models, in addition to tissue from patients, to explore the genetics and biochemistry behind these diseases. “Our typical experiments start off with seeing how long we can keep cells with damaged mitochondria alive,” Barrow says. “We put them under certain nutrient conditions we know will kill them because they can’t make ATP. Then we try to promote survival by treating them with small molecules or by modifying certain genes.”
Once they’ve established which compounds can rescue the cells, Barrow and her collaborators move on to the discovery phase of their research. “We have to figure exactly what the compound does,” Barrow says. “What is it binding? How is it targeting this function? How is it boosting ATP production? To maximize the potential for therapy, we need to answer questions like those. At the same time, we might discover other additional factors that show therapeutic potential along the way.”
“My lab is looking at genetic and molecular components to discover if some people have a predisposition that makes them more or less obese.”
Barrow is following up on her earlier work as a postdoctoral researcher at Harvard University, where she profiled 10,015 small molecules — naturally occurring and synthesized compounds that target various proteins in the body. She and her colleagues identified more than 100 promising chemical compounds. Now her lab is characterizing them to evaluate their ability to correct mitochondrial damage, specifically in muscle cells. So far, a significant subset has a positive effect, and the researchers are trying to pin down exactly how they work.
Obesity and Metabolic Diseases, Mitochondria-Related
Continuing her research connected to mitochondria, Barrow also explores metabolic disease in the context of obesity. Worldwide, 1.9 million, or one in three people, are overweight, and 41 million of them are children under the age of five. With obesity comes associated metabolic diseases such as cancer, cardiovascular disease, and hypertension.
“Every year we do the statistics on obesity, and no matter how much we counsel on diet and exercise, no matter how easy it should be to maintain an energetic balance, something is amiss,” Barrow says. “So my lab is looking at genetic and molecular components to discover if some people have a predisposition that makes them more or less obese or to see if we can take advantage of the molecular system to increase energy expenditure. This could offer another form of therapy to fight against obesity in conjunction with diet and exercise.”
The researchers have turned their attention to thermogenic fat. This subset of fat cells, also called brown and beige fat, is prevalent in animals that go through hibernation, but scientists recently discovered it in humans as well. “Brown and beige fat don’t only store fat molecules, like white fat does, they have a special ability to burn them to produce heat,” Barrow explains.
Thermogenic fat has a protein known as uncoupling protein 1 that pokes a hole in the membrane of mitochondria, allowing protons to leak out. These protons are part of a proton gradient that is integral to the production of ATP. Without them, mitochondria are no longer able to effectively make the chemical. “Your body’s response is to start burning everything it can to try to maintain the proton gradient,” Barrow says. “And as a result, your energy expenditure goes through the roof.”
Brown fat is prevalent in newborn humans where it serves to keep infants from going into thermal shock as they exit from maternal body temperature to the much colder temperature outside the womb. Later, other mechanisms, such as shivering, serve to keep adults warm while maintaining their body weight. “But adults still have brown fat that we can activate to increase energy expenditure components,” Barrow explains.
Using proteomics, metabolomics, and genomics, Barrow and her colleagues seek to unveil factors that will activate brown and beige fat cells. “We have discovered a host of novel genes that are involved in turning on the thermogenic pathway that protects you against obesity,” Barrow says. “Now it will be fascinating to discover how these genes work so that they can be targeted toward therapy.”
For Barrow, who has a doctorate in biochemistry and molecular biology, with clinical expertise as a registered dietitian, mitochondria are a perfect target for research. “The mitochondria are the metabolic hub of the cell,” she says. “No matter what aspect of metabolism you study — lipids, carbohydrates, vitamins — they all feed back into whether or not you can effectively produce energy. Everything my lab works on centers around this very mighty, tiny organelle that’s so important to life.”