Lipid droplet–mitochondria mismatch in atherosclerosis: From disrupted lipid routing to persistent inflammation and necrotic core expansion

Abstract

Atherosclerosis (AS) is a chronic lipid-driven inflammatory disease of the arterial wall, and substantial cardiovascular risk persists despite intensive lipid-lowering therapy. Plaque progression depends not only on lipid entry, but also on how vascular wall cells handle intracellular lipids under sustained stress. Lipid droplets (LDs) temporarily sequester excess cholesteryl ester and triacylglycerol, whereas mitochondria use part of the mobilized fatty acid pool and sustain metabolic adaptation. The protective value of LD storage therefore depends on whether it remains linked to effective downstream processing and disposal. Here, lipid droplet-mitochondria (LD-Mito) mismatch describes a loss of coordination between LD turnover and mitochondrial substrate handling. In the plaque environment, this mismatch can shift lipid fate from adaptive buffering toward persistent retention and oxidative injury, thereby reinforcing inflammation and necrotic remodeling. This review examines LD remodeling in macrophages, vascular smooth muscle cells, and endothelial cells; mitochondrial substrate limitation and quality-control imbalance; and the context-dependent regulation of the LD-Mito axis. It further considers how disrupted lipid handling intersects with trained immunity, lipid peroxidation, cell death, and defective efferocytosis. Therapeutically, reducing LD abundance or increasing mitochondrial oxidation in isolation may be insufficient. More effective strategies may require cell- and lesion-specific restoration of coordinated lipid handling while preserving redox control and clearance capacity. The LD-Mito perspective reframes residual plaque risk around a central question: whether intracellular lipids can still reach tolerable downstream fates under sustained atherogenic stress.