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SMRT-depleted conventional DCs maintain inflammation despite lower glycolysis via mTOR signalling and succinate

Kaushik Sen1,2, Rashmirekha Pati1, Gyan Prakash Mishra1

  • 1Immunogenomics & Systems Biology Lab, Institute of Life Sciences (ILS), Bhubaneswar, Odisha, 751023, India.

Npj Metabolic Health and Disease
|July 3, 2025
PubMed

Insights

Loss of SMRT in dendritic cells causes inflammation by altering immune cell metabolism, contrary to current understanding. Targeting succinate oxidation and mTOR pathways suppressed this inflammation, suggesting new therapeutic avenues for autoimmune diseases.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Cellular metabolism

Background:

  • Immune homeostasis relies on coordinated immune-metabolic adaptations.
  • Regulatory mechanisms of metabolic adjustments in dendritic cells (DCs) are not fully understood.
  • Loss of Ncor2 (SMRT) in DCs was previously shown to potentiate inflammation.

Purpose of the Study:

  • To elucidate the transcriptional control of immune-centric metabolic adjustments in DCs.
  • To investigate the metabolic consequences of SMRT loss in DCs.
  • To identify potential therapeutic targets for SMRT-mediated inflammation.

Main Methods:

  • Investigated metabolic shifts in SMRT-depleted DCs.
  • Analyzed the role of mTOR in regulating glycolytic rate.
  • Examined alterations in the TCA-cycle, including glutamine catabolism and succinate oxidation.
  • Evaluated the efficacy of DEBM and Mhy1485 in suppressing inflammation ex vivo and in vivo.

Main Results:

  • SMRT depletion in DCs induced a metabolic shift, causing sustained inflammation despite reduced glycolysis.
  • mTOR downregulation was identified as a key factor in attenuating the glycolytic rate.
  • Rewiring of the TCA-cycle involved increased glutamine catabolism and succinate oxidation, sustaining inflammation.
  • Simultaneous treatment with DEBM and Mhy1485 significantly suppressed inflammation.
  • An inverse correlation was observed between SMRT levels and human autoimmune diseases.

Conclusions:

  • SMRT loss in DCs triggers inflammation through a unique metabolic rewiring, challenging the established role of glycolysis.
  • Targeting succinate oxidation and mTOR pathways offers a potential therapeutic strategy for inflammatory and autoimmune diseases.
  • SMRT represents a potential biomarker and therapeutic target in human autoimmune conditions.

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