Targeting Mitochondrial Dysfunction to Prevent Endothelial Dysfunction and Atherosclerosis in Diabetes: Focus on the Novel Uncoupler BAM15

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, leading to endothelial dysfunction and accelerated atherosclerosis. Mitochondrial dysfunction, oxidative stress, and dysregulated lipid metabolism contribute to endothelial cell (EC) injury, promoting plaque formation and increasing cardiovascular disease risk. Current lipid-lowering therapies have limited effectiveness in restoring endothelial function, highlighting the need for novel strategies. Mitochondrial uncoupling has emerged as a promising approach, with BAM15-a newly identified mitochondrial uncoupler-showing potential therapeutic benefits. BAM15 enhances fatty acid oxidation (FAO), reduces reactive oxygen species, and protects ECs from hyperglycemia-induced apoptosis. Unlike conventional uncouplers, BAM15 demonstrates improved tolerability and efficacy without severe off-target effects. It restores mitochondrial function, improves endothelial survival, and supports metabolic homeostasis under hyperglycemic conditions. This review uniquely integrates emerging evidence on mitochondrial dysfunction, endothelial metabolism, and FAO to highlight the novel role of BAM15 in restoring vascular function in diabetes. We provide the first focused synthesis of BAM15's mechanistic impact on EC bioenergetics and position it within the broader landscape of mitochondrial-targeted therapies for diabetic vascular complications. Further research is needed to elucidate the molecular mechanism through which BAM15 modulates EC metabolism and to evaluate its long-term vascular effects in diabetic models.

Keywords: atherosclerosis; diabetes mellitus; endothelial dysfunction; mitochondrial dysfunction; mitochondrial uncoupling.

Figure 1

Endothelial cells (ECs) facilitate low-density lipoprotein (LDL) transcytosis into the subendothelial space, initiating a vascular inflammatory response. In early atherosclerosis, the endothelium shifts from a quiescent to activated state in response to pro-atherogenic stimuli such as oxidized LDL (ox-LDL), pro-inflammatory cytokines, and disturbed flow. Activated ECs recruit immune cells, including T lymphocytes, neutrophils, and monocytes, into the intima. Monocyte-derived macrophages engulf lipids to form foam cells, which undergo necrosis and apoptosis, contributing to the lipid core of growing plaques. Increased endothelial permeability further facilitates LDL entry into the arterial wall, a key early event in plaque initiation, progression, and eventual rupture.

Figure 2

Schematic of atherosclerotic plaque formation from a healthy artery to plaque rupture, highlighting the most critical events that lead to its development at each stage. Diabetes, hypertension, dyslipidemia, vascular inflammation, and endothelial dysfunctions are all variables that contribute to plaque formation and rupture. Atherosclerosis develops gradually as cholesterol, fat, blood cells, and other blood components combine to produce plaque. When plaque builds up in the arteries, it causes them to narrow. This reduces the transport of oxygen-rich blood to tissues and vital organs in the body.

Figure 3

Schematic illustration showing the potential protective effects of BAM15 against atherosclerosis by enhancing EC function under hyperglycemic conditions. BAM15 mitigates mitochondrial damage by regulating membrane potential, reducing ROS, and inhibiting apoptosis. Through mild mitochondrial uncoupling, BAM15 increases energy expenditure, promotes FAO, and reduces intracellular lipid accumulation. These effects suggest BAM15 may serve as an effective therapeutic strategy for diabetes-associated atherosclerosis.