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Succinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism
Aenne-Dorothea Liebing1, Philipp Rabe1, Petra Krumbholz1
1Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, Germany.
The FEBS Journal
|January 22, 2025
Summary
Succinate receptor 1 (SUCNR1) signaling is influenced by cellular metabolism, affecting inflammation and energy balance. Its location and activation depend on energy sources like glucose or glutamine.
Area of Science:
- Cellular metabolism and signaling pathways.
- G protein-coupled receptor (GPCR) function.
- Immunometabolism and inflammation.
Background:
- Succinate is a key metabolite in the tricarboxylic acid cycle.
- Succinate activates the succinate receptor 1 (SUCNR1), a Gi- and Gq-coupled receptor.
- SUCNR1 signaling has reported contradictory anti- or pro-inflammatory effects.
Purpose of the Study:
- To investigate the link between cellular metabolism and SUCNR1 signaling localization.
- To understand how different energy substrates affect SUCNR1 activation and downstream signaling.
- To resolve conflicting reports on succinate's role in inflammation.
Main Methods:
- Bioluminescence resonance energy transfer (BRET)-based biosensors.
- Dynamic mass redistribution (DMR) measurements.
- Second messenger assays, kinase phosphorylation assays, and calcium imaging.
- Metabolic analyses under varying energy substrates (glucose/glutamine).
Main Results:
- SUCNR1 signaling, localization, and cellular metabolism are interdependent.
- Glutamine consumption enhances oxidative phosphorylation, increasing extracellular succinate and SUCNR1 internalization.
- SUCNR1 exhibits distinct Gi/Gq protein activation dependent on spatial localization and energy substrate.
- SUCNR1 interacts with G proteins within endosomal compartments.
- In M2-like macrophages, SUCNR1-mediated Gi signaling stimulates glycolysis, while Gq signaling inhibits it.
Conclusions:
- Cellular metabolic state dictates SUCNR1's spatial signaling.
- SUCNR1 signaling modulates cellular energy homeostasis in response to succinate levels.
- Metabolic context is crucial for understanding SUCNR1's diverse roles in inflammation and cell function.
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