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Metabolic rewiring during bone development underlies tRNA m7G-associated primordial dwarfism.
Li, Qiwen; Jiang, Shuang; Lei, Kexin; Han, Hui; Chen, Yaqian; Lin, Weimin; Xiong, Qiuchan; Qi, Xingying; Gan, Xinyan; Sheng, Rui; Wang, Yuan; Zhang, Yarong; Ma, Jieyi; Li, Tao; Lin, Shuibin; Zhou, Chenchen; Chen, Demeng; Yuan, Quan.
Afiliación
  • Li Q; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Jiang S; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Lei K; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Han H; Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Chen Y; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Lin W; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Xiong Q; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Qi X; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Gan X; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Sheng R; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Wang Y; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Zhang Y; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Ma J; Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Li T; West China-Washington Mitochondria and Metabolism Center and Department of , West China Hospital, Sichuan University, Chegndu, China.
  • Lin S; Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Zhou C; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • Chen D; Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • Yuan Q; State Key Laboratory of Oral Diseases & National Center for Stomatology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Clin Invest ; 2024 Sep 10.
Article en En | MEDLINE | ID: mdl-39255038
ABSTRACT
Translation of mRNA to protein is tightly regulated by tRNAs, which are subject to various chemical modifications that maintain the 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 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 of incompetent proliferation and osteogenic commitment. Further exploration revealed that impaired Rho GTPase signaling upregulated branched-chain amino acid transaminase 1 (BCAT1) level 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 either by targeting 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 regulating cellular metabolism, and indicates that suspension of translation initiation as quality control mechanism in response to tRNA dysregulation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos