Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial biogenesis

• Published in: Molecular pain 2024-01, Vol.20, p.17448069241252654-17448069241252654
• Main Authors: Xu, Lingfei, Tang, Xihui, Yang, Long, Chang, Min, Xu, Yuqing, Chen, Qingsong, Lu, Chen, Liu, Su, Jiang, Jinhong
• Format: Article
• Language: English
• Subjects: Adenosine kinase; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Biosynthesis; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetic Neuropathies - drug therapy; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - pathology; Diabetic neuropathy; Dorsal horn; Glucose metabolism; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Inflammation; Kinases; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Microglia - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Organelle Biogenesis; Pain perception; Peptides; Peptides - pharmacology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxisome proliferator-activated receptors; Phosphorylation; Protein kinase; Sensitivity analysis; Signal transduction; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology; Streptozocin
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1177/17448069241252654

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.