Succinate drives macrophage inflammation by promoting GPR91 mitochondrial signaling in rheumatoid arthritis.

High succinate concentrations are implicated in rheumatoid arthritis (RA) and other inflammatory diseases through G protein-coupled receptor 91 (GPR91)-mediated signaling. Despite the therapeutic potential of targeting GPR91, conflicting reports on the receptor's inflammatory roles have hindered treatment development. Here, we report that the effects of succinate on GPR91 signaling are biphasic and concentration dependent. At physiological succinate concentration, membrane-localized GPR91 promotes M2 polarization through Gq-mediated activation of phospholipase C and intracellular calcium mobilization. In RA, elevated succinate induces GPR91 internalization and mitochondrial translocation, thereby disrupting Gq signaling. Mechanistically, mitochondrial GPR91 recruits Gs proteins and, together with intracellular succinate, activates the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway. PKA then phosphorylates cytidine/uridine monophosphate kinase 2 at serine-404, stabilizing it to enhance mitochondrial DNA (mtDNA) synthesis. Newly synthesized mtDNA is oxidized (forming ox-mtDNA) and released into the cytosol, activating the cyclic GMP-AMP synthase-stimulator of interferon genes pathway to drive macrophage inflammation. Myeloid-specific GPR91 deletion or inhibition of intracellular succinate accumulation alleviates arthritis in mice. This study reveals that GPR91 reprograms signaling by subcellular relocation, providing a promising therapeutic strategy for autoimmune diseases.