2. Academic Validation
  3. Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells

Estradiol alleviates disease phenotypes caused by m.3635G > a mutations by activating mitochondrial biogenesis and PINK1-Parkin mediated mitophagy in iPSC-derived retinal pigment epithelium cells

  • Cell Signal. 2025 Sep 8:136:112121. doi: 10.1016/j.cellsig.2025.112121.
Chao Hu 1,  Tianhong Su 2,  Ying Zhang 3,  Jing Yang 3,  Xun Su 3,  Zhikang Zhang 3,  Xin Wang 3,  Weiwei Zou 4,  Dan Liang 4,  Yajing Liu 4,  Dongmei Ji 5,  Yunxia Cao 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, China.
  • 2 Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China.
  • 4 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, China; The First Affiliated Hospital of Anhui Medical University, Center for Big Data and Population Health of IHM, No. 81 Meishan Road, Hefei 230032, Anhui, China; Anhui Provincial Institute of Translational Medicine, No. 81 Meishan Road, Hefei 230032, Anhui, China.
  • 5 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, China; The First Affiliated Hospital of Anhui Medical University, Center for Big Data and Population Health of IHM, No. 81 Meishan Road, Hefei 230032, Anhui, China; Anhui Provincial Institute of Translational Medicine, No. 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: jidongmei@ahmu.edu.cn.
  • 6 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230032, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No. 81 Meishan Road, Hefei 230032, Anhui, China; The First Affiliated Hospital of Anhui Medical University, Center for Big Data and Population Health of IHM, No. 81 Meishan Road, Hefei 230032, Anhui, China; Anhui Provincial Institute of Translational Medicine, No. 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: caoyunxia5972@ahmu.edu.cn.
PMID: 40930474 DOI: 10.1016/j.cellsig.2025.112121
Abstract

Leber's hereditary optic neuropathy (LHON), a mitochondrial disorder marked by central vision loss, exhibits incomplete penetrance and male predominance. Since there are no adequate models for understanding the rapid vision loss associated with LHON, we generated induced pluripotent stem cells (iPSCs) from LHON patients carrying the pathogenic m.3635G > A mutation and differentiated them into retinal pigment epithelium (RPE) cells. The mutation disrupted mitochondrial dynamics, suppressing OPA1-mediated fusion and enhancing DRP1-dependent fission, resulting in decreased expression of ND1, ND5, NDUFB8, SDHB and COX2, impaired mitochondrial bioenergetic function, and cell proliferation. Additionally, the m.3635G > A mutation promoted intrinsic Apoptosis, altered autophagic flux, evidenced by elevating levels in apoptotic proteins PARP1, Caspase-3, and 9, reduced levels of Autophagy protein LC3-II, and increased levels of substrate p62. Moreover, the m.3635G > A mutation inhibited PINK1-Parkin-dependent Mitophagy. Based on sex-specific differences in hormone metabolism, we proposed that estrogen plays a protective role in women and showed that Estrogen receptor α and β were downregulated in LHON. We demonstrated that estradiol improved cell viability by reducing Apoptosis, inducing mitochondrial biogenesis through the PGC1α-NRF1/2-TFAM axis, and vigorously promoting PINK1-Parkin-dependent Mitophagy in LHON iPSCs and iPSC-derived RPE cells. Our findings have highlighted the critical role of the m.3635G > A mutation in the pathogenetic process of LHON, and our observations support the hypothesis that estrogen is helpful in the preventive treatment of LHON.

Keywords

Autophagy; Induced pluripotent stem cell; Leber's hereditary optic neuropathy (LHON); Mitochondrial disease; Mitophagy; mtDNA mutation.

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