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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Postmenopausal ovarian hormone deficiency (OHD) contributes to overactive bladder (OAB) through oxidative stress, mitochondrial dysfunction, and dysregulated estrogen receptor (ER) signaling. This study investigated whether estradiol (E2) alleviates dysfunction by modulating the ER\/Smad\/miRNA-200\/KLF4\/mTOR signaling pathway to restore mitochondrial quality control. Thirty female Sprague-Dawley rats were initially allocated to Sham, Ovariectomy (OVX) and OVX + E2 group; after attrition during the 12-month protocol, six surviving animals per group were included in the principal analyses. The OVX + E2 group received daily intramuscular E2 (IM, 30 \u03bcg\/kg\/day) for one month. Bladder function was assessed via micturition volume and frequency by metabolic cages, cystometrograms, and contractility assays. Mechanisms were analyzed using immunofluorescence, Western blotting, transmission electron microscopy (TEM), and miRNA sequencing. OVX rats exhibited significant overactivity and compromised contractility, accompanied by upregulated ER\u03b1 and downregulated ER\u03b2\/GPER. Molecularly, OHD was associated with the upregulation of the miRNA-200 family (miRNA-200a-3p, miRNA-200b-3p and miRNA-200b-5p), which was accompanied by reduced levels of KLF4 and autophagy proteins (ATG7, ATG12 and Beclin-1), as well as elevated p-mTOR expression. TEM revealed the accumulation of damaged mitochondria with ultrastructural features associated with impaired mitophagy. However, E2 treatment ameliorated these abnormalities. These improvements were associated with the restoration of TGF-\u03b2\/Smad signaling, downregulation of selected miRNA-200 family members, recovery of KLF4 level, and increased expression of autophagy-related markers, accompanied by improved mitochondrial ultrastructural integrity. This cellular restoration might be correlated with improved urodynamic parameters. E2 might exert therapeutic effects by improving mitochondrial quality, potentially via the ER\/Smad\/miRNA-200\/KLF4 signaling pathway. These findings provided mechanistic insights into estrogen-mediated protection and highlight this proposed signaling pathway as a therapeutic target for postmenopausal OAB.<\/jats:p>","DOI":"10.3390\/ijms27177529","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:47:19Z","timestamp":1787572039000},"page":"7529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Estradiol Ameliorates Postmenopausal Bladder Dysfunction by Restoring Mitophagy via the miRNA-200\/KLF4\/mTOR Signaling Pathway"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0307-5131","authenticated-orcid":false,"given":"Kuang-Shun","family":"Chueh","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9108-7567","authenticated-orcid":false,"given":"Jian-He","family":"Lu","sequence":"additional","affiliation":[{"name":"Emerging Compounds Research Center, Department of Environmental Science and Engineering, College of Engineering, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Wen","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6593-5120","authenticated-orcid":false,"given":"Bin-Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1102-0512","authenticated-orcid":false,"given":"Cheng-Yu","family":"Long","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 80708, Taiwan"},{"name":"Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, 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