RBM43 controls PGC1α translation and a PGC1α-STING signaling axis

Cell Metab. 2025 Mar 4;37(3):742-757.e8. doi: 10.1016/j.cmet.2025.01.013. Epub 2025 Feb 17.

Abstract

Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

Keywords: PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism.

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • DNA, Mitochondrial / metabolism
  • Energy Metabolism
  • Humans
  • Inflammation / metabolism
  • Male
  • Membrane Proteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Nucleotidyltransferases / metabolism
  • Obesity / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
  • Protein Biosynthesis
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Signal Transduction

Substances

  • RNA-Binding Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Membrane Proteins
  • Sting1 protein, mouse
  • Ppargc1a protein, mouse
  • Nucleotidyltransferases
  • DNA, Mitochondrial