Enzymes were in different locations in mitochondria of diabetic and nondiabetic rats.
Image credit: Partha Banerjee/Johns Hopkins Medicine
Researchers from Johns Hopkins University (JHU), Baltimore, MD, say the discovery could lead to new ways of preventing and treating diabetes.
They describe how they uncovered the cause and effect link between high blood sugar and metabolic disease in a paper published in the Proceedings of the National Academy of Sciences.
Corresponding author Gerald Hart, professor in biological chemistry at the JHU School of Medicine, explains:
"Sugar itself isn't toxic, so it's been a mystery why high blood sugar can have such a profound effect on the body."
He says they found high blood sugar appears to disrupt the function of a molecule involved in numerous cell processes.
Other teams have already established that in untreated diabetes, high blood sugar changes how mitochondria work, so the JHU team decided to take a look at the underlying molecular processes.
Large difference in mitochondrial enzyme levels between diabetic and nondiabetic rats
For their study, the team compared the enzymes in mitochondria from the hearts of rats with diabetes to those from healthy rat hearts.
They focused on two enzymes that add and remove a molecule called O-GlcNAc to and from proteins.
Prof. Hart's group has spent the last 30 years researching how cells use O-GlcNAc to control processing of nutrients and energy.
They found that one of the enzymes - O-GlcNAc transferase, that adds the molecule to proteins - was present at higher levels in the mitochondria of diabetic rats. At the same time, levels of the other enzyme - O-GlcNAcase, that removes the molecule from proteins - were lower.
First author Dr. Partha Banerjee, a postdoctoral fellow in Hart's lab who carried out the experiments, notes their surprise at the finding:
"We expected the enzyme levels to be different in diabetes, but we didn't expect the large difference we saw."
The team also found that O-GlcNAc transferase was in a different place in the mitochondria of the diabetic animals. Instead of being embedded in the walls of the mitochondria, they found much of the enzyme had migrated to the inside.
Net effect is to lessen the efficiency of energy production in mitochondria
The study also shows how the two enzymes play other significant roles in mitochondria, such as in producing chemical units of energy to cells in the form of ATP.
Prof. Hart says the net effect of these O-GlcNAc-related changes is to lessen the efficiency of energy production in mitochondria, causing them to produce more heat and damage-causing molecules.
This causes the liver to trigger antioxidants to neutralize the damage-causing molecules, which in turn produces more glucose, spiraling blood sugar even further.
Prof. Hart suggests the finding could lead to new treatments to prevent and treat diabetes that target the O-GlcNAc enzymes.
Funds for the study came from the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases.
Prof. Hart declared a commercial interest in the study - he receives royalties on sales of one of the antibodies used in the experiments.
Meanwhile, scientists are starting to discover mitochondria do more than provide cells with energy.
For example, Medical News Today recently learned of a study in Nature Cell Biology, led by researchers from NYU Langone Medical Center, NY, that reveals how mitochondria control stem cell development.
The team found that blocking the action of a key enzyme in mitochondria stopped stem cells from developing into egg cells in fruit flies.