Metabolic rewiring during bone development underlies tRNA m7G–associated primordial dwarfism
Qiwen Li, … , Demeng Chen, Quan Yuan
Qiwen Li, … , Demeng Chen, Quan Yuan
Published September 10, 2024
Citation Information: J Clin Invest. 2024;134(20):e177220. https://doi.org/10.1172/JCI177220.
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Research Article Bone biology Metabolism

Metabolic rewiring during bone development underlies tRNA m7G–associated primordial dwarfism

Abstract

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 N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7G 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 m7G-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 α-ketoglutarate (αKG). Supplementation of αKG 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 m7G 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.

Authors

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

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Figure 1

Deletion of Mettl1 impairs skeletal growth.

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Deletion of Mettl1 impairs skeletal growth. (A) Representative skeletal ...
(A) Representative skeletal staining of WT and Prrx1Cre Mettl1fl/fl mouse forelimbs at E14.5, E16.5, and E18.5. (B) Representative Alcian blue staining of WT and Prrx1Cre Mettl1fl/fl mouse humerus at E14.5, E18.5, and P7. Hypertrophic zone is magnified. Scale bars: 200 μm (left) and 40 μm (right). (C) Quantification of humerus length at E14.5, E16.5, and E18.5. n = 3. (D and E) Representative immunostaining and quantification of collagen type X (Col10) and matrix metalloproteinase 13 (MMP13) of WT and Prrx1Cre Mettl1fl/fl humerus at E16.5. Scale bars: 200 μm. (F and G) Representative EdU labeling and quantification of WT and Prrx1Cre Mettl1fl/fl mouse femur at E16.5. Boxed areas are magnified. Scale bar: 200 μm. (H and I) Representative immunostaining and quantification of Sp7 of WT and Prrx1Cre Mettl1fl/fl mouse humerus at E16.5. Scale bars: 100 μm. Data are expressed as mean ± SEM; **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test.