Blockade of T-type Ca2+ channels disrupts mitochondrial function and follicle development by inhibiting the PI3K/AKT pathway

Calcium signaling through T-type channels is essential for ovarian function. This study reveals that blocking these channels disrupts follicle development and hormone production by impairing mitochondrial function and suppressing the phosphatidylinositol 3-kinase/protein kinase B pathway in mice. AbstractCalcium (Ca2+) functions as a critical secondary messenger in cellular signaling and is essential for maintaining ovarian function and promoting oocyte maturation. However, the contribution of T-type voltage-gated calcium channels (VGCCs) to ovarian follicle development remains unclear. To investigate this, we administered flunarizine (FNZ), a potent T-type VGCCs antagonist, to 4-6-week-old female mice via intraperitoneal injection at doses of 0, 3, or 30 mg/kg/day for 7 days. FNZ exposure significantly impaired ovarian morphology, disrupted folliculogenesis, and induced estrous cycle irregularities, concomitant with a marked reduction in serum 17β-estradiol (E2) levels. FNZ led to diminished intracellular Ca2+ levels and mitochondrial dysfunction, resulting in attenuated ATP production. Notably, ovarian tissues exhibited elevated DNA damage, as indicated by increased γH2AX expression. Transcriptomic analysis revealed pronounced alterations in Fibroblast Growth Factor 1 signaling-related genes. Furthermore, FNZ inhibit activation of protein kinase B (p-AKT), an effect that was rescued by recilisib, a specific activator of phosphatidylinositol 3-kinase (PI3K)/Akt. In conclusion, our study establishes that pharmacological inhibition of T-type VGCCs disrupts hormonal secretion and follicular development in adolescent mice, likely through modulation of the PI3K/Akt signaling axis.

FGF1; PI3K/AKT; flunarizine; granulosa cells; mitochondria; ovary.