Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.

Abstract

Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.