Targeting N1-methyladenosine modification in osteoblasts through tRNA methyltransferase 10C reverses mitochondrial dysfunction and ameliorates osteoporosis

Osteoporosis is among the most common degenerative systemic bone diseases and is accompanied by abnormally downregulated oxidative phosphorylation (OXPHOS) in osteoblasts. While mutations in the tRNA methyltransferase ( TRMT10C ) gene in humans are known to cause OXPHOS dysfunction and early mortality, its role in bone homeostasis remains unknown. Here, we observed markedly reduced expression of TRMT10C, which is encoded by the nuclear genome, and OXPHOS subunits, which are encoded by the mitochondrial (mt) genome, in osteoblasts from both age-related and estrogen deficiency-induced osteoporosis mice. Conditional knockout of Trmt10c in osterix-expressing osteoprogenitor cells resulted in growth retardation, bone loss, and spontaneous fractures. Critically, through a multistage in silico screening approach, we identified a novel small-molecule compound as a TRMT10C agonist for the first time. Pharmacological activation of TRMT10C by this compound significantly promoted bone formation and ameliorated osteoporotic phenotypes in both aged and ovariectomized mice. Mechanistically, this study provides the first evidence that TRMT10C can bind to and catalyze the N 1 -methyladenosine (m 1 A) modification of mt-rRNA, in addition to its known role in catalyzing the m 1 A modification of mt-tRNA and mt-mRNA. This study reveals a previously unknown role for TRMT10C in bone metabolism and identifies it as a promising therapeutic target for osteoporosis.