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

Area of Science:

• Toxicology
• Bone Biology
• Mitochondrial Medicine

Background:

• Uranium exposure is linked to bone metabolism disruption.
• Bone marrow mesenchymal stem cells (BMSCs) are vital for bone homeostasis.
• The specific impact of uranium on BMSCs is not well understood.

Purpose of the Study:

• To investigate the effects of long-term uranium exposure on BMSCs and bone metabolism.
• To elucidate the mechanisms underlying uranium-induced bone damage.
• To evaluate potential therapeutic interventions.

Main Methods:

• Micro-CT analysis and histological staining in mice.
• RNA sequencing of uranium-treated BMSCs.
• Immunofluorescence staining and Transmission Electron Microscopy (TEM).
• Administration of nicotinamide mononucleotide (NMN) and a chelating agent (TAM-2LI-MAM2, LNN).

Main Results:

• Uranium accumulation in bone led to osteopenia, reduced bone formation, increased adipogenesis, and osteoclast activity.
• Uranium dysregulated genes related to oxidative phosphorylation, mitochondrial function, inflammation, and fat metabolism in BMSCs.
• Mitochondrial dysfunction, particularly Complex I impairment, induced senescence and SASP secretion in BMSCs.
• NMN partially rescued uranium-induced senescence by improving mitochondrial function.
• The chelating agent LNN restored bone mass and improved bone formation.

Conclusions:

• Long-term uranium exposure induces osteopenia via mitochondrial dysfunction-driven senescence in BMSCs.
• Therapeutic strategies targeting mitochondrial function and uranium chelation may offer benefits for uranium-induced bone toxicity.