Mitochondrial Metabolism in Neutrophils: Emerging Roles in Inflammatory Skin Diseases.

Abstract

Neutrophils, the most abundant of the circulating leucocytes, play crucial roles in antimicrobial defence, tissue remodelling, and immune regulation. Traditionally regarded as predominantly glycolytic, relying on aerobic glycolysis (the Warburg effect) for rapid ATP generation, neutrophils are now recognised to possess broader metabolic flexibility. Emerging evidence has revealed their capacity for oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glutaminolysis. As a result, mitochondrial metabolism is dynamically reprogrammed during differentiation and activation. These metabolic shifts in mitochondria profoundly influence essential neutrophil functions, including extracellular trap (NET) formation, reactive oxygen species (ROS) generation, chemotaxis, and apoptosis. In inflammatory skin diseases, mitochondrial dysfunction amplifies pathological responses by enhancing ROS production and driving NETosis. Specifically, in conditions such as psoriasis, cutaneous lupus erythematosus, and Behçet's disease, neutrophil mitochondrial activity is markedly increased, and this increase correlates with disease activity and progression. Notably, mitochondrial ROS have emerged as critical mediators of inflammation, triggering pathways such as PAD4 (peptidylarginine deiminase type 4)-dependent NETosis, inflammasome activation, and proinflammatory cytokine release. Accordingly, therapeutic strategies targeting neutrophil mitochondrial pathways, including ROS scavengers, mitophagy inducers, and metabolic modulators, are gaining increasing attention as promising approaches to mitigate neutrophil-driven skin inflammation. In this review recent advances in understanding mitochondrial metabolism in neutrophils, with particular emphasis on the pathological roles and therapeutic potential of this metabolism as related to inflammatory skin disorders are described.