Targeting Mitochondria Reduces Atherosclerosis Associated With Cardiometabolic Syndrome

Atherosclerosis associated with cardiometabolic syndrome is particularly complex because its development involves insulin resistance, excess triglycerides, fat accumulation in the liver, and inflammation of the arterial wall. A study involving the Sant Pau Research Institute (IR Sant Pau) shows that simultaneously targeting several of these mechanisms can reduce the progression of atherosclerosis, both during the early stages of plaque formation and once lesions are already established, in an experimental mouse model.

The study, published in Science Translational Medicine, focused on CRMP, an oral controlled-release formulation that moderately alters mitochondrial function to promote greater fat oxidation by cells. In treated animals, this strategy reduced triglyceride levels, improved insulin sensitivity, and limited inflammation in macrophages within the plaques, resulting in smaller lesions with features consistent with greater stability.

The study was led by Dr. Leigh Goedeke of the Icahn School of Medicine at Mount Sinai and included the participation of Dr. Noemí Rotllan, currently a researcher at IR Sant Pau and the Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), who began collaborating on this research while at Yale University. “Most importantly, the benefit is not limited to correcting a specific metabolic abnormality. It also improves the environment in which the plaque develops while reducing the inflammatory response within the lesion,” explains Dr. Rotllan.

Mild and Controlled Mitochondrial Uncoupling

CRMP is a controlled-release formulation of 2,4-dinitrophenol designed to maintain low and sustained exposure to the compound. Its mechanism of action is based on mitochondrial uncoupling, a process that slightly reduces the efficiency with which mitochondria convert nutrients into the energy cells need to function.

As a result, cells must oxidize more fat to obtain the same amount of energy, which may help reduce lipid accumulation in tissues such as the liver and muscle. Previous studies had shown that this strategy could improve insulin resistance, hypertriglyceridemia, and fat accumulation in the liver in different animal models, but its effect on the progression of atherosclerosis had not been studied in this level of detail.

The researchers evaluated the treatment in mice genetically predisposed to developing atherosclerosis and fed a diet high in fat and cholesterol. This model reproduces several abnormalities characteristic of cardiometabolic syndrome, including insulin resistance, hypertriglyceridemia, hepatic steatosis, and the progressive formation of arterial plaques.

Lower Triglyceride Levels and Improved Insulin Response

The treatment reduced triglycerides carried by VLDL and LDL lipoproteins, partly because of decreased hepatic production of triglyceride-rich VLDL. However, it did not produce significant changes in total cholesterol, HDL cholesterol, or the animals’ body weight, indicating that its effects cannot be explained by weight loss or an overall reduction in cholesterol.

CRMP also improved insulin sensitivity in the liver and muscle. Analyses showed reduced accumulation of certain lipids in the membranes of liver and muscle cells. These molecules, known as diacylglycerols, can interfere with insulin signaling when they accumulate in excess.

“Insulin resistance and hypertriglyceridemia are not isolated abnormalities. They are part of the metabolic environment that promotes plaque growth and inflammation. Improving this environment may therefore have a direct effect on the progression of vascular disease,” explains Dr. Rotllan.

Reducing these lipids improved insulin’s ability to suppress glucose production in the liver and promote its use in muscle. The treatment therefore targeted metabolic abnormalities closely associated with cardiovascular risk that are not always corrected by therapies directed exclusively at cholesterol.

Smaller Plaques and Reduced Vascular Inflammation

The metabolic improvements were accompanied by a reduction in the extent of atherosclerotic plaques, decreased lipid accumulation, and smaller necrotic cores—the area of the lesion composed of dead cells and lipid debris. Plaques in treated animals also had larger fibrous caps and fewer macrophages, features consistent with potentially more stable lesions.

The study also indicates that CRMP can act directly on macrophages, immune cells that accumulate in plaques and contribute to persistent vascular inflammation. In these cells, mitochondrial uncoupling reduced the production of reactive oxygen species and limited activation of the inflammasome, a molecular complex that promotes the release of interleukin-1 beta, a cytokine involved in the progression of atherosclerosis.

The researchers observed reduced activation of proteins involved in this process and lower levels of interleukin-1 beta within the lesions. However, the treatment did not significantly alter the number of circulating leukocytes or plasma levels of this cytokine, suggesting that its effect is concentrated primarily on local inflammation in the arterial wall without causing widespread suppression of the immune response.

Effects on Established Lesions

To better approximate the clinical setting, the authors evaluated CRMP both from the onset of plaque formation and after the animals had developed atherosclerosis, hypertriglyceridemia, and insulin resistance.

In both scenarios, the treatment reduced lesion progression. When administered at more advanced stages, it decreased the size of the plaques and their necrotic cores, reduced lipid accumulation and the presence of inflammatory macrophages, and increased the area of the fibrous cap.

“The fact that the treatment also reduces the progression of established lesions is particularly relevant because it more closely reflects the clinical setting, in which interventions begin after atherosclerosis has already developed,” notes Dr. Rotllan.

The results indicate that this strategy may not only act during the early stages of the disease but also slow its progression once lesions are already present. However, the study does not demonstrate the complete disappearance or regression of plaques, but rather reduced progression compared with animals that did not receive the treatment.

CRMP also failed to reduce atherosclerosis in a second animal model that did not have such pronounced metabolic abnormalities. This finding indicates that its benefits probably depend on the coexistence of factors such as insulin resistance, hypertriglyceridemia, and fat accumulation in the liver, and that its potential use may be particularly relevant to atherosclerosis associated with cardiometabolic syndrome.

“These results are promising, but this is still a preclinical study. The next step will be to confirm the efficacy and safety of this strategy in models that more closely resemble human physiology and to assess whether it could eventually complement current treatments to reduce the cardiovascular risk associated with cardiometabolic syndrome,” concludes Dr. Rotllan.

Reference Article:

Dos Santos BG, Brisnovali NF, Haney C, Coven M, Sebzevari HL, Gaebel L, Zhang X, Sun J, Canfrán-Duque A, Rotllan N, Nasiri A, Kahn M, McAlpine CS, Shulman GI, Goedeke L. A controlled-release mitochondrial protonophore attenuates early- and late-stage atheroprogression in mice. Sci Transl Med. 2026 Jul 15. doi:10.1126/scitranslmed.adv1815.