Higher Succinate Levels Trigger Receptor Relocation, Revealing a Mechanism of Rheumatoid Inflammation

Researchers in South Korea have identified a mechanism by which the metabolite succinate, which triggers inflammation in rheumatoid arthritis (RA), promotes inflammation by changing the location and signaling of its receptor depending on its concentration.

Yang Xuezhi, Weiwei and Chang Yan’s team at Anhui Medical University reported the findings on the 12th (local time) in the international journal Science Translational Medicine.

According to the team, succinate has a dual, concentration-dependent effect on G protein-coupled receptor 91 (GPR91). At physiological concentrations, GPR91 located on the cell membrane induces M2 macrophage polarization through Gq proteins.

In RA, however, succinate concentrations rise sharply. Succinate concentrations in the synovial fluid of patients with RA were found to be more than 10 times higher than those in healthy controls.

At higher concentrations, GPR91 moves inside the cell and relocates to the mitochondria, blocking Gq signaling. GPR91 relocated to the mitochondria 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 (CMPK2) at serine 404, stabilizing it and increasing mitochondrial DNA (mtDNA) synthesis.

The newly synthesized mtDNA is oxidized to form ox-mtDNA and released into the cytoplasm. It then activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, triggering macrophage inflammation.

The team reported that arthritis in mice was alleviated when GPR91 was selectively deleted in myeloid cells or intracellular succinate accumulation was inhibited.

The researchers said, “We confirmed that GPR91 reprograms signaling through subcellular relocation,” adding, “This could be a promising therapeutic strategy for autoimmune diseases.”