Journal Article

Metabolic rewiring during bone development underlies tRNA m.sup.7G-associated primordial dwarfism

Jiang, Shuang, Chen, Yaqian, Lin, Weimin, Qi, Xingying, Yuan, Quan, Xiong, Qiuchan, Wang, Yuan, Han, Hui, Li, Tao, Sheng, Rui, Ma, Jieyi, Li, Qiwen, Lei, Kexin, Lin, Shuibin, Gan, Xinyan, Chen, Demeng, Zhou, Chenchen, Zhang, Yarong

2024

Overview

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA [N.sup.7]-methylguanosine ([m.sup.7]G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of [m.sup.7]G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of [m.sup.7]G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular [alpha]-ketoglutarate ([alpha]KG). Supplementation of [alpha]KG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of [m.sup.7]G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation.

• Publisher: American Society for Clinical Investigation
• Subject: Bones / Branched chain amino acids / Density / Dwarfism / Enzymes / Genetic aspects / Genetic translation / Health aspects / Medical research / Medicine, Experimental / Metabolism / Physiological aspects / Scientific equipment and supplies industry / Transfer RNA