Metabolomics

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


ABSTRACT:

Succinate is implicated in rheumatoid arthritis (RA) and other inflammatory diseases via its receptor, G protein-coupled receptor 91 (GPR91). Despite its therapeutic potential, conflicting reports on its inflammatory roles have hindered GPR91-targeted treatments. Here, we report that the effects of succinate are biphasic and concentration-dependent. At physiological levels, membrane-localized GPR91 promotes M2 polarization through Gq-mediated activation of phospholipase C and subsequent 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 (PK)-A pathway. PKA then phosphorylates ctidine/uridine monophosphate kinase 2 at Ser404, 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 via subcellular relocation, uncovering a novel therapeutic strategy for autoimmune diseases.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse-phase

PROVIDER: MTBLS13828 | MetaboLights | 2026-02-05

REPOSITORIES: MetaboLights

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