Desmopressin Induces Mitochondrial Fragmentation and Dysfunction in Human U87 MG Glioma Cells via CaMKII‐Drp1 Signaling Pathway

Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog, on mitochondrial function in human U87 MG glioma cells. Our results demonstrate that dDAVP treatment induces dose-dependent cytotoxicity while upregulating vasopressin type 2 receptor expression. The compound significantly increased oxidative stress markers and impaired mitochondrial function, as evidenced by reduced ATP production, compromised respiratory chain activity, and decreased oxygen consumption. Furthermore, dDAVP promoted mitochondrial fragmentation through Drp1 activation, enhancing its phosphorylation at Ser616 and subsequent mitochondrial translocation. Mechanistically, dDAVP was found to activate CaMKII signaling, which mediated the observed changes in Drp1 phosphorylation and mitochondrial dynamics. The CaMKII inhibitor KN-93 effectively reversed dDAVP-induced mitochondrial fragmentation, Drp1 phosphorylation, and energy metabolism impairment. The AVPR2 antagonist tolvaptan blocked dDAVP effects, confirming receptor specificity. These findings reveal that dDAVP disrupts mitochondrial homeostasis in glioma cells through AVPR2-mediated CaMKII-dependent regulation of Drp1 activity, leading to mitochondrial dysfunction and cell damage. The study provides new insights into the molecular mechanisms underlying dDAVP's effects on glioma cells and suggests potential therapeutic applications targeting the CaMKII-Drp1 axis in glioma treatment.