A recent study from researchers at the Johns Hopkins University School of Medicine — published Oct. 26 in Cell Chemical Biology — indicates that newly designed AMPK-targeting peptides Pa496h and Pa496m may improve mitochondrial dynamics and high blood glucose levels in people with diabetes, obesity and age-related metabolic disorders based on findings from mice and human cells.

Declining mitochondrial activity contributes to the accumulation of toxic biochemicals and can lead to weight gain. In the United States, obesity is estimated to affect 4 out of 10 adults, and is a major risk factor for type 2 diabetes. Childhood obesity, often an early indicator of metabolic diseases such as diabetes in adulthood, is estimated to affect 1 in 5 Americans between the ages of 2 and 19.

Disturbances and disorders of mitochondria, the cellular powerhouses also responsible for the use and breakdown of nutrients, have long been a target of medical efforts to prevent, slow down or reverse declines of healthy mitochondrial populations.

The researchers explain that mitochondria in all mammals continuously undergo fusion and fission — combining and splitting — the processes necessary to maintain a healthy cell population. Aging and obesity are marked by elongated mitochondria, which can impair their activity and overall function. Until now, the researchers say, there hasn’t been a direct way to stimulate mitochondrial fission without causing serious mitoch ondrial damage and a reduction in nutrient metabolism.                                         

They successfully designed two AMPK-targeting peptides, Pa496h and Pa496m. Both are involved in the activation of AMPK, the master regulator of cellular metabolism, by blocking the negative phosphorylation (the attachment of a phosphate group to a molecule) of AMPK at serine 496. Next, activated AMPK upregulates a signaling pathway to initiate mitochondrial fission, a process that breaks the big mitochondria (megamitochondria) found in diabetes, obesity and age-related metabolic disorders, and then stimulates the removal of damaged mitochondria after mitochondrial fission. These effects of Pa496h and Pa496m can lead to a healthy mitochondrial population and improvement of mitochondrial metabolism and activity.

These targeting peptides can also reduce the accumulation of harmful substances, such as reactive oxygen species, which are toxic to cells.

In the obese mouse models and in hepatocytes (main functional cells of the liver) from obese patients, these targeting peptides can inhibit the excessive glucose production in liver hepatocytes, the major cause of high blood glucose levels in obesity and diabetes.

“Our experiments show our targeting peptides can not only enhance and restore mitochondrial function, but also improve their high blood glucose levels, potentially making it particularly valuable for elderly individuals struggling with obesity and diabetes by lowering blood sugar levels,” says Ling He, associate professor of pediatrics and pharmacology.

By promoting mitochondrial fission with the innovative peptides, the researchers’ aim is to reduce weight gain and combat obesity in both children and adults. Future research will focus on the use of Pa496h and Pa496m peptides to promote mitochondrial fission in brown fat (or brown adipose tissue, is a type of body fat that regulates your body temperature in cold conditions), in particular, to increase mitochondrial number, activity and metabolism, and thus to burn more nutrients and to control weight gain in obesity.

These studies received support from the National Institutes of Health, and there are no conflicts of interest to disclose.

This technology is available for licensing and corporate partnerships.