Mice fed a high-sugar, high-fat diet for most of their lives managed to escape weight gain and protect their livers when they were treated with an experimental new drug.

The small-molecule drug was developed by a team led by The University of Texas Health Science Center at San Antonio (UT Health San Antonio). Known by its chemical acronym CPACC, it works by limiting the entry of magnesium into the mitochondria, the parts of the cell in charge of generating energy and burning calories.

Mitochondrial abnormalities have been implicated in a range of diseases, including obesity, diabetes, and cardiovascular disease.

"These findings are the result of several years of work," says UT Health San Antonio molecular biochemist Madesh Muniswamy, senior author of the published paper reporting the results.

Along with calcium, potassium, and sodium, magnesium is one of the four major positively charged ions that contribute to cellular functions in the body in multiple ways. In fact magnesium plays many important roles in maintaining health, such as regulating blood sugar and blood pressure and helping construct strong bones. But too much magnesium slows energy production in mitochondria.

"It puts the brake on, it just slows down," says biologist Travis Madaris from UT Health San Antonio, co-lead author of the paper.

The researchers discovered the new drug while studying the effect of deleting a specific gene called MRS2, which encodes a magnesium transporter protein called Mrs2. This protein acts as a channel to transport magnesium across the mitochondrial membrane.

They investigated the effects of a long-term high-fat, high-sugar, and high-calorie Western diet on normal mice compared to mice whose MRS2 gene was deleted.

MRS2 deletion led to leaner, healthier mice with improved sugar and fat metabolism in their mitochondria, despite consuming the Western diet starting at 14 weeks of age, for up to a year (a long time in a mouse's life).

When it comes to regulating sugar and fat metabolism in response to eating and fasting, the liver is in the driver's seat. Though a fairly robust organ, it has its limits. Tellingly, there were no signs of fatty liver disease in the liver or fat tissues of the MRS2 deletion mice, which can result from an unbalanced diet, obesity, or type 2 diabetes.

"Lowering the mitochondrial magnesium mitigated the adverse effects of prolonged dietary stress," says biologist and third co-lead author Manigandan Venkatesan from UT Health San Antonio.

In further experiments with administration of CPACC, the team reported the same effects as deletion of the MRS2 gene. The drug works by inhibiting the magnesium channels that the gene encodes for. Again it resulted in lean, healthy mice by reducing the amount of magnesium transported into the mitochondria.

Of course, results in mice don't necessarily apply to humans, and the authors of the study note that it has some limitations. To mimic metabolic syndrome in humans, their method uses long-term dietary stress. Putting the system through short-term dietary stress could help clarify the main effects of MRS2 deletion.

Also, the researchers say that using a complete deletion method for MRS2 makes it impossible to look at how each tissue affects metabolic regulation. Given MRS2's widespread expression, they emphasize the importance of further research into its effects on various organs like the brain, heart, kidneys, lungs, and skeletal muscles.

The researchers have filed a patent application on CPACC.

"A drug that can reduce the risk of cardiometabolic diseases such as heart attack and stroke, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will make a huge impact," Muniswamy says.

"We will continue its development."

The research has been published in Cell Reports.