Uranium exposure induces osteopenia via mitochondrial dysfunction-driven senescence in bone marrow mesenchymal stem cells

Uranium primarily accumulates in the bone over the long-time exposure, and studies in both humans and animal models have shown that it disrupts bone metabolism and function. Bone marrow mesenchymal stem cells (BMSCs) play crucial roles in bone homeostasis and can differentiate into osteoblasts, chondrocytes and adipocytes. However, the effect of uranium on BMSCs remains obscure. Here, we showed that long-term accumulation of uranium in the femur caused loss of bone mass with reduction of bone formation and increased adipogenesis and osteoclast activity in mice as determined by micro-CT analysis and histological staining. RNA sequencing analysis revealed that oxidative phosphorylation, mitochondrial function, inflammation and fat metabolism related genes were dysregulated in BMSCs treated with uranium. Similarly, immunofluorescence staining and TEM exhibited mitochondrial and oxidative phosphorylation impairment especially mitochondrial Complex I dysfunction. Of note, the mitochondrial dysfunction resulted in SASP secretion and senescence in BMSCs which can inhibit bone formation and enhance adipogenesis and osteoclast activity. Administration of nicotinamide mononucleotide (NMN) as NAD⁺ precursor partially rescued uranium induced senescence in BMSCs through enhancing mitochondrial complex I activity and mitochondrial function. Compared to uranium treated mice, declining uranium concentration in bone with a potent chelating agent TAM-2LI-MAM 2 (L NN ) , bone mass and number of trabecular bone were recovered with enhanced bone formation and reduction of adipogenesis. Taken together, our results demonstrate that long-term accumulation of uranium in bone resulted in osteopenia with reduction of bone formation and increased adipogenesis and osteoclast activity through mitochondrial dysfunction-driven senescence. • Long-term uranium accumulation in bone is a primary driver of progressive osteopenia. • Uranium exposure induces mitochondrial dysfunction within bone marrow mesenchymal stem cells. • Mitochondrial damage triggers cellular senescence, which directly impairs bone formation. • Chelation of accumulated uranium rescues stem cell function and restores bone mass.