MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated <?A3B2 pi6?>mitochondrial biogenesis

作者：Long Yang, Miaomiao Li, Yucheng Liu, Yang Bai, Tianyu Yin, Yangyang Chen, Jinhong Jiang, Su Liu · 发表于：Acta Biochimica et Biophysica Sinica · 年份：2024 · DOI：10.3724/abbs.2024048 · 被引用次数：10 · 研究领域：Histone Deacetylase Inhibitors Research、Cancer, Stress, Anesthesia, and Immune Response、Pain Management and Opioid Use

Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα 1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, pr...