Dumesic Phillip A, Wilensky Sarah E, Bose Symanthika, Van Vranken Jonathan G, Gygi Steven P, Spiegelman Bruce M
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cell Metab. 2025 Mar 4;37(3):742-757.e8. doi: 10.1016/j.cmet.2025.01.013. Epub 2025 Feb 17.
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.
肥胖与损害线粒体功能的全身炎症相关。这种破坏会减少氧化代谢，限制脂肪细胞的脂质代谢和产热，产热是一种将化学能以热量形式消散的有益代谢过程。在此，我们表明，线粒体生物发生的关键调控因子PGC1α在其mRNA翻译水平受到RNA结合蛋白RBM43的负调控。RBM43由炎性细胞因子诱导，并以PGC1α依赖的方式抑制线粒体生物发生。在小鼠中，脂肪细胞选择性敲除Rbm43可提高PGC1α的翻译水平和氧化代谢。在肥胖状态下，Rbm43缺失可改善葡萄糖耐量，减轻脂肪炎症，并抑制脂肪细胞中固有免疫传感器cGAS-STING的激活。我们进一步确定了PGC1α在防止线粒体DNA（一种cGAS配体）在细胞质中积累方面的作用。RBM43的作用定义了一个翻译调控轴，通过该轴炎症信号决定细胞能量代谢，并促进代谢性疾病的发病机制。
