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

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis

Phillip A Dumesic  1 , Sarah E Wilensky  2 , Symanthika Bose  2 , Jonathan G Van Vranken  3 , Steven P Gygi  3 , Bruce M Spiegelman  4
Affiliations

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis

Phillip A Dumesic et al. Cell Metab. .

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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