It’s Not Rewarding for Mitochondria: Dopamine-Induced Mitochondrial Dysfunction Activates cGAS-STING to Drive IL-6 Secretion in Macrophages

Summary Despite increasing data demonstrating dopamine as an inflammatory mediator of the innate immune system, the molecular mechanisms underlying its effects in human cells remain incompletely defined. Here, we define an unrecognized pathway in which dopamine induces robust IL-6 secretion in primary human monocyte-derived macrophages (hMDMs) through mitochondrial stress. Dopamine initiates a transient mitochondrial membrane depolarization that leads to sustained alterations in mitochondrial dynamics, including morphology and metabolism, in a time-dependent manner. These events promote the mtDNA release into the cytoplasm, triggering cGAS-STING pathway and downstream NF-κB signaling. Pharmacological inhibition at multiple nodes of this pathway attenuates IL-6 secretion, establishing mitochondrial dysfunction and cGAS-STING signaling as central mediators of dopamine-driven IL6 secretion. Variability in dopamine receptor expression across donors correlates with the magnitude of IL-6 responses. Together, these findings redefine the interface between dopamine signaling and systemic inflammation and highlight an unrecognized source of inter-individual variation in immune responses. Graphical Abstract Dopamine induces mitochondrial dysfunction mediated through dopamine receptors’ signaling. This includes alterations in mitochondrial membrane potential, leading to excessive DRP1-mediated mitochondrial fission, increased production of mitochondrial superoxide, and metabolic reprogramming toward enhanced glycolysis with reduced oxidative phosphorylation. Sustained mitochondrial damage is further exacerbated by impaired mitophagy, resulting in the release of mitochondrial DNA (mtDNA) into the cytoplasm. Cytosolic mtDNA, acting as a double-stranded DNA ligand, activates the cGAS-STING pathway, which subsequently induces NF-κB signaling, ultimately driving the production and secretion of the pro-inflammatory cytokine IL-6. Created on Biorender.com. Competing Interest Statement The authors have declared no competing interest.