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

• Published in: Acta biochimica et biophysica Sinica Vol. 56; pp. 1323 - 1339
• Main Authors: Yang Long, Li Miaomiao, Liu Yucheng, Bai Yang, Yin Tianyu, Chen Yangyang, Jiang Jinhong, Liu Su
• Format: Journal Article
• Language: English
• Published: China Science Publishing & Media Ltd 01.05.2024
• Subjects: AMPK; bone cancer pain; mitochondrial; MOTS-c; osteoclast
• ISSN: 1672-9145
• DOI: 10.3724/abbs.2024048

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, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.