Researchers at UT Health San Antonio, along with collaborators from the University of Pennsylvania and Cornell University, have developed a small-molecule drug called CPACC that limits the transport of magnesium into cellular powerhouses called mitochondria. The drug has been shown to prevent weight gain and unwanted liver changes in mice on a high-sugar and high-fat diet. By reducing magnesium transport into the mitochondria, the drug improves sugar and fat metabolism, resulting in leaner, healthier mice with no signs of fatty liver disease. The researchers have filed a patent application for the drug, which has potential implications in reducing the risk of cardiometabolic diseases and liver cancer.
The compound limits the transport of magnesium into cellular powerhouses called mitochondria.
A small-molecule drug, CPACC, developed by researchers, has been shown to prevent weight gain and liver problems in mice by limiting the transport of magnesium into cellular powerhouses, thereby improving metabolism and health overall.
Researchers at the University of Texas San Antonio Health Science Center (UT Health San Antonio) have developed a small molecule drug that prevents weight gain and unwanted liver changes in mice fed a western diet high in sugar and fat throughout their lives.
“When we give mice this drug for a short time, they start to lose weight. They’re all getting thin,” said Madesh Muniswamy, PhD, professor of medicine at the Joe R. and Teresa Lozano Long School of Medicine at the Health Sciences Center.
“A drug that can reduce the risk of cardiometabolic diseases such as heart attacks and strokes, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will have a huge impact.” — Madesh Muniswamy, PhD
The findings of the collaborators, also from the University of Pennsylvania and Cornell University, were recently published in the high-impact journal Cell reports. Muniswamy, director of the Center for Mitochondrial Medicine at UT Health San Antonio, is the lead author.
Fourth most common item
The research team discovered the drug by first exploring the impact of magnesium on metabolism, ie the production and consumption of energy in cells. This energy, called ATP, powers the body’s processes.
Magnesium is the fourth most abundant cation, or positively charged ion, in the body after calcium, potassium, and sodium, and plays many key roles in good health, including regulating blood sugar and blood pressure. and bone building. But researchers have found that too much magnesium slows energy production in the mitochondria, which are the powerhouses of cells.
“It brakes, it just slows it down,” said co-lead author Travis R. Madaris, a doctoral student in the Muniswamy Lab at UT Health San Antonio.
Deleting MRS2, a gene that promotes magnesium transport into the mitochondria, led to more efficient sugar and fat metabolism in powerhouses. The result: lean and healthy mice.
Liver and adipose (fatty) tissue from the rodents showed no signs of fatty liver disease, a complication linked to poor diet, obesity and type 2 diabetes.
Microscopic image of mitochondria in a single heart cell. Mitochondria highlighted in red were exposed to ultraviolet light. Credit: National Heart, Lung and Blood Institute, National Institutes of Health
Small molecule agent
The drug, which the researchers call CPACC, accomplishes the same thing. It limits the amount of magnesium transfer in power plants. In the experiments, the result was again: lean, healthy mice. UT Health San Antonio has filed a patent application on the drug.
The mice served as a model system of long-term dietary stress precipitated by the high-calorie, sugary, and fatty Western diet. The well-known results of this stress are obesity, type 2 diabetes and cardiovascular complications.
“The reduction in mitochondrial magnesium attenuated the adverse effects of prolonged dietary stress,” said co-lead author Manigandan Venkatesan, PhD, postdoctoral fellow in the Muniswamy lab.
Joseph A. Baur, PhD, of the University of Pennsylvania and Justin J. Wilson, PhD, of Cornell are among the collaborators. “We found the small molecule and Justin synthesized it,” Madaris said.
Magnesium acts as a brake on energy production, researchers have found.
Important consequences
“These findings are the result of several years of work,” Muniswamy said. “A drug that can reduce the risk of cardiometabolic diseases such as heart attacks and strokes, and also reduce the incidence of liver cancer, which can follow fatty liver disease, will have a huge impact. We will pursue its development.
Reference: “Mrs2-dependent mitochondrial Mg limitation2+ absorption induces metabolic programming in prolonged dietary stress” by Travis R. Madaris, Manigandan Venkatesan, Soumya Maity, Miriam C. Stein, Neelanjan Vishnu, Mridula K. Venkateswaran, James G. Davis, Karthik Ramachandran, Sukanthathulse Uthayabalan, Cristel Allen, Ayodeji Osidele, Kristen Stanley, Nicholas P. Bigham, Terry M. Bakewell, Melanie Narkunan, Amy Le, Varsha Karanam, Kang Li, Aum Mhapankar, Luke Norton, Jean Ross, M. Imran Aslam, W. Brian Reeves, Brij B. Singh, Jeffrey Caplan, Justin J. Wilson, Peter B. Stathopulos, Joseph A. Baur and Muniswamy Madesh, February 27, 2023, Cell reports.
DOI: 10.1016/j.celrep.2023.112155
Funders of this project include the National Institutes of Health, the US Department of Defense and the San Antonio Partnership for Precision Therapeutics.