Magnesium Channel Blocker CPACC Reverses Obesity and Fatty Liver Disease in Mice on Western Diet
Key Insights
A small-molecule compound called CPACC (search) that blocks mitochondrial magnesium transport prevented obesity (search) and liver damage in mice fed a long-term Western diet.
Mice lacking the MRS2 (search) magnesium channel stayed lean, showed browning of white fat, and were protected from fatty liver disease (search) and liver tumors.
CPACC (search) injections every three days for six weeks limited weight gain and improved liver function markers in diet-challenged mice.
Researchers at The University of Texas Health Science Center at San Antonio have identified a small-molecule compound that appears to counteract weight gain and metabolic damage in mice exposed to a long-term Western diet. The drug candidate, called CPACC (search), kept mice from becoming obese even after prolonged exposure to a sugar-rich, fat-heavy diet, and also protected the animals from liver damage linked to poor nutrition, including fatty buildup and tumor formation.
The work, published in Cell Reports, points to an unexpected target: magnesium movement inside mitochondria, the energy-producing structures found in cells.
"When we give this drug to the mice for a short time, they start losing weight. They all become slim," said Madesh Muniswamy, PhD, professor of medicine at the Joe R. and Teresa Lozano Long School of Medicine and director of the Center for Mitochondrial Medicine at UT Health San Antonio. Muniswamy was the study's senior author.
Why Mitochondrial Magnesium Became the Focus
Magnesium is essential for life, helping regulate blood sugar and blood pressure, supporting bone health, and participating in numerous chemical reactions. It is the fourth most abundant cation in the body. But inside mitochondria, the study suggests, too much magnesium may act less like fuel and more like a brake.
When magnesium enters mitochondria through a channel controlled by a gene called MRS2 (search), it can slow the cell's ability to burn sugar and fat efficiently. "It puts the brake on, it just slows down," said co-lead author Travis R. Madaris, a doctoral student in Muniswamy's lab.
To test the idea, researchers removed the MRS2 (search) gene in mice and fed them a Western diet for as long as 52 weeks. Normal mice gained weight and developed signs of metabolic disease. Mice without MRS2 stayed lean, despite eating similar amounts of food, drinking similar amounts of water, and moving about as much as the other animals. Their metabolism also appeared more active: the mice were better able to use sugar and fat for energy, and their white fat began showing signs of "browning," a shift toward a more energy-burning type of fat.
Protection Beyond Body Weight
The liver results were especially dramatic. In typical mice, the Western diet led to fatty liver changes, fibrosis, liver enlargement, and frequent liver tumors. Those problems were largely absent in mice lacking MRS2 (search). Their liver and adipose tissues showed no evidence of fatty liver disease (search), a condition closely tied to obesity (search), type 2 diabetes (search), and poor diet. The animals also maintained healthier blood glucose levels and avoided several signs of diet-induced metabolic syndrome.
The researchers found that reducing magnesium entry into mitochondria changed how cells handled citrate, a molecule used to make fat. With less mitochondrial magnesium, less citrate appeared to leave the mitochondria for fat production. That shift may help explain why the mice accumulated less fat in the liver and body.
A Drug That Copies the Genetic Effect
The team then tested CPACC (search), which blocks magnesium transport through the same mitochondrial pathway. UT Health San Antonio has filed a patent application for the drug.
In experiments, CPACC (search) reduced lipid buildup in liver cells, increased mitochondrial respiration, lowered plasma citrate, and promoted features of beige fat, a more metabolically active form of fat. In mice on a high-fat diet, injections of CPACC every three days for six weeks limited weight gain and improved a marker of liver function.
"Lowering the mitochondrial magnesium mitigated the adverse effects of prolonged dietary stress," said co-lead author Manigandan Venkatesan, PhD, a postdoctoral fellow in the Muniswamy lab.
The collaboration was essential to developing the compound. Joseph A. Baur, PhD, of the University of Pennsylvania, and Justin J. Wilson, PhD, of Cornell University (search), were among the contributors. "We came up with the small molecule and Justin synthesized it," Madaris said.
What This Could Mean for Future Treatments
The results suggest that mitochondrial magnesium channels may be a promising target for obesity (search), fatty liver disease (search), type 2 diabetes (search), and other cardiometabolic conditions. Still, the findings are early. The main experiments were done in mice, and the study used a global MRS2 (search) knockout, which means the researchers could not isolate the role of the channel in each individual tissue. The authors also note that future work will need safer, more refined MRS2 modulators suitable for human studies.
"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 attack and stroke, and also reduce the incidence of liver cancer, which can follow fatty liver disease (search), will make a huge impact. We will continue its development."
Broader Implications of Mitochondrial Magnesium Transport
Related studies published after the CPACC (search) work suggest that mitochondrial magnesium transport may matter beyond obesity (search) and fatty liver disease (search). A 2024 Mitochondrion study showed that lower magnesium levels inside mitochondria increased activity of the mitochondrial calcium uniporter (MCU), which controls calcium uptake into mitochondria. The finding helps explain how mitochondrial magnesium can influence calcium signaling, energy production, and cell stress.
In 2026, a Hypertension study connected Mrs2 (search) to pulmonary arterial hypertension (search) (PAH). In diseased pulmonary artery cells, excess mitochondrial magnesium helped drive metabolic dysfunction, lactate buildup, calcium overload, mitochondrial damage, and abnormal cell growth. Reducing Mrs2 activity improved mitochondrial function and eased vascular remodeling in rats.