Metabolic control of immunity and inflammation: Mitochondrial dynamics, pharmacological targets, and therapeutic opportunities

Immune responses and inflammation are not stand-alone processes linearly regulated by the canonical signaling pathways but complex systems biology events, which are deeply rooted in the metabolic state of cells and dynamically modulated. However, immunometabolic studies have identified that programmed alterations of metabolic circuits also occur during activation of immune cells, effector function maintenance and the induction of tolerance. Mitochondria represent a unique point of convergence between energetics, inflammation and immunity, particularly as they are key orchestrators of immune responses. In addition to their classical roles in oxidative phosphorylation (OXPHOS) and metabolic intermediate synthesis, mitochondria are involved in innate immune perception of inflammatory signals and the amplification of these responses by generating reactive oxygen species (ROS), bioenergetic signaling intermediates, and mitochondrial DNA. Crucially, mitochondria are not stable entities but are tightly regulated by dynamic events such as fusion, fission, trafficking and selective degradation. These structural alterations dynamically influence the metabolic commitment, inflammatory response potency and fate choices of immune cells. Mitochondrial dynamics should not be regarded as a mere auxiliary regulatory layer of immunometabolism; instead, they represent the central organizing principles between metabolic states, inflammatory cues, and immune cell fate determination, thereby defining a new hierarchical organization of immune and inflammatory regulation.