Researchers link energy metabolism in cells with changes in disease expression
Scientists with the Fralin Biomedical Research Institute at VTC have revealed how different levels of a mitochondrial genetic mutation could cause a rare form of adult-onset diabetes in some people and a childhood-onset progressive neurodegenerative disorder in others.
The difference between progressive developments of two diseases may lie in the discrete energy metabolism of the cells.
The findings, published online in April in the journal Scientific Reports, could raise understanding of a condition called Maternally Inherited Diabetes - a mitochondrial disease passed from mothers to their children. Around 1 to 3 percent of all diabetes cases are caused by this genetic mutation.
“When 30 percent of the mitochondrial DNA in cells carry this genetic mutation, they synthesize energy as well as breakdown glucose and fatty acids at a much higher rate compared with cells with normal mitochondrial DNA,” said senior author Sarika Srivastava, a research assistant professor at the Fralin Biomedical Research Institute. “However, when nearly 100 percent of the mitochondrial DNA in cells carry this genetic mutation, the rates of cellular energy production as well as glucose and fatty acids breakdown are significantly impaired compared with cells with normal mitochondrial DNA.”
Researchers examined the mitochondrial metabolic gene expression profiles and function in engineered human transmitochondrial (cytoplasmic hybrid) cells containing either a low or high level of the mitochondrial transfer RNA leucine genetic mutation, known as m.3243A>G. This genetic mutation is associated with Maternally Inherited Diabetes or MELAS, which stands for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes that is a highly debilitating and devastating disease.
Mitochondria are tiny “energy producing factories” that are present in almost every cell of our body. They contain their own DNA referred to as mitochondrial DNA, which exists in hundreds to thousands of copies per cell. Typically, less than 45 percent of the mitochondrial DNA copies per cell carry the genetic mutation in diabetes, compared with more than 85 percent in MELAS, the researchers said.
Diabetes, which affects more than 30 million Americans, according to the National Institute of Diabetes and Digestive and Kidney Diseases, occurs when someone’s blood sugar is too high. These high sugar levels increase the risk of other health problems, such as heart disease, stroke, nerve damage, eye problems, and kidney disease.
On the other hand, MELAS syndrome affects the body’s brain, nervous system, and muscles, often causing stroke-like weakness on one side of the body.
“Our findings are the first to suggest that these different disease traits could arise because the energy metabolic function of the cells is different when the cells have high levels of this genetic mutation than when they have low levels,” Srivastava said.
Researchers say their findings may advance the understanding of the potential mechanisms by which low levels of this genetic mutation could progressively cause diabetes, which is an important step along a path towards potentially developing preventive or therapeutic interventions down the road.
The study was supported by the Fralin Biomedical Research Institute and the Virginia Tech open access subvention fund. In addition to faculty with the Fralin Biomedical Research Institute, the study also involved faculty from two Virginia Tech colleges.
Srivastava collaborated with Ryan McMillan, a research assistant professor in the Department of Human Nutrition, Foods and Exercise in the Virginia Tech College of Agriculture; Sidney Stewart, formerly a student working at the Fralin Biomedical Research Institute and now with the Edward Via College of Osteopathic Medicine in Auburn, Alabama; Clayton Caswell, an associate professor in the Department of Biomedical Sciences and Pathobiology and the Center for One Health Research of the Virginia Maryland College of Veterinary Medicine; James Budnick, formerly a graduate research assistant at the Center for One Health Research; Matthew Hulver, co-director of the Fralin Biomedical Research Institute Center for Transformative Research on Health Behaviors and the head of the Department of Human Nutrition, Foods and Exercise; and Konark Mukherjee, an assistant professor at the Fralin Biomedical Research Institute.