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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.<\/jats:p>\n                  <jats:p>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\u20136-week-old female mice via intraperitoneal injection at doses of 0, 3, or 30\u2009mg\/kg\/day for 7\u2009days. FNZ exposure significantly impaired ovarian morphology, disrupted folliculogenesis, and induced estrous cycle irregularities, concomitant with a marked reduction in serum 17\u03b2-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 \u03b3H2AX 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.<\/jats:p>","DOI":"10.1093\/reprod\/xaag028","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:44:35Z","timestamp":1772023475000},"source":"Crossref","is-referenced-by-count":0,"title":["Blockade of T-type Ca2+ channels disrupts mitochondrial function and follicle development by inhibiting the PI3K\/AKT pathway"],"prefix":"10.1093","volume":"171","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1483-3981","authenticated-orcid":false,"given":"Xiuling","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4745-6511","authenticated-orcid":false,"given":"Shiqin","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8979-0526","authenticated-orcid":false,"given":"Ting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4380-983X","authenticated-orcid":false,"given":"Xuhui","family":"Zeng","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3839-2447","authenticated-orcid":false,"given":"Liping","family":"Pu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Guangxi University , Guangxi,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7643-6439","authenticated-orcid":false,"given":"Junyu","family":"Nie","sequence":"additional","affiliation":[{"name":"Institute of Reproductive Medicine, Medical School, Nantong University , Jiangsu,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"2026032113415505800_xaag028-B1","doi-asserted-by":"publisher","first-page":"4503","DOI":"10.1210\/jc.2003-032219","article-title":"Two types of calcium channels in human ovarian endocrine cells: involvement in steroidogenesis","volume":"89","author":"Agoston","year":"2004","journal-title":"The Journal of Clinical Endocrinology and Metabolism"},{"key":"2026032113415505800_xaag028-B2","doi-asserted-by":"publisher","first-page":"E184","DOI":"10.1152\/ajpendo.2002.282.1.E184","article-title":"Effect of basal lamina of ovarian follicle on T- and L-type Ca2+ currents in differentiated granulosa cells","volume":"282","author":"Asem","year":"2002","journal-title":"American Journal of Physiology. 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