Targeting Mitochondrial Dysfunction to Treat Diabetic Osteoporosis: Role of Neoprzewaquinone A

Diabetic osteoporosis (DMOP) involves impaired bone formation driven by mitochondrial dysfunction and osteoblast apoptosis. Current treatments do not address these mechanisms.

To evaluate whether Neoprzewaquinone A (NEO), a natural compound from Salvia miltiorrhiza, can protect bone by restoring mitochondrial integrity and activating survival signaling.

Bioinformatics, molecular docking, and biophysical assays were combined with in vitro and in vivo studies. Mouse osteoblasts were exposed to glucolipotoxic conditions, and DMOP was induced in C57BL/6 mice. NEO's effects on mitochondrial morphology, mitochondrial membrane potential, ATP production, ROS, apoptosis markers, and PI3K/AKT/mTOR signaling were assessed using imaging, flow cytometry, western blotting, and micro-CT.

Glucolipotoxic stress caused mitochondrial damage, ROS accumulation, and suppression of ELF5/PRKD2 and PI3K/AKT/mTOR signaling. NEO bound PRKD2 with high affinity (KD ≈ 10⁻⁶ M), restored pathway activation, reduced ROS, attenuated HGPA-induced mitochondrial depolarization, restored ATP levels, and preserved mitochondrial ultrastructure. In diabetic mice, oral NEO improved bone mineral density, trabecular architecture, and mechanical strength without detectable toxicity.

NEO mitigates diabetic bone loss by rescuing mitochondrial function and activating the ELF5/PRKD2/PI3K/AKT/mTOR axis. These findings highlight mitochondrial protection as a promising strategy for DMOP therapy and position NEO as a candidate for mechanism-based treatment.