Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway
Oxidative stress (OS) is regarded as a major contributor to granulosa cellapoptosis in ovarian disease. 1-Deoxynojirimycin (1-DNJ), a naturally occurring plant alkaloid, exhibits antioxidant, anti-inflammatory, and metabolism-modulating properties. Mitochondria and endoplasmic reticulum (ER), crucia...
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2025-04-01
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| author | Wenwen Xing Mengxuan Li Binbin Wang Lele Huo Wanru Tian Fangcai Ge Manman Shen Liumei Sun Jiying Liu Shali Yu |
| author_facet | Wenwen Xing Mengxuan Li Binbin Wang Lele Huo Wanru Tian Fangcai Ge Manman Shen Liumei Sun Jiying Liu Shali Yu |
| author_sort | Wenwen Xing |
| collection | DOAJ |
| description | Oxidative stress (OS) is regarded as a major contributor to granulosa cellapoptosis in ovarian disease. 1-Deoxynojirimycin (1-DNJ), a naturally occurring plant alkaloid, exhibits antioxidant, anti-inflammatory, and metabolism-modulating properties. Mitochondria and endoplasmic reticulum (ER), crucial organelles regulating oxidative balance, interact through mitochondria-associated endoplasmic reticulum membranes (MAMs) for signaling and molecular exchange. However, it remains unclear whether 1-DNJ attenuates oxidative damage in ovarian granulosa cells (GCs) via MAMs-mediated ER–mitochondria crosstalk, which needs further exploration. This study aimed to investigate the mechanisms by which 1-DNJ affects oxidative damage and apoptosis induced by OS in porcine follicular GCs by regulating mitochondrial function, MAMs, and ER interactions. Here, we found that GCs suffered from OS, accompanied by the up-regulation of ROS and MDA, alongside reduced activity of antioxidant enzymes (CAT and T-SOD). Further studies revealed that the up-regulation of MAMs proteins (MFN2, MCU, and VDAC1) and pro-apoptosis proteins (BAX and Cleaved-capase3), along with increased mitochondrial ROS and Ca<sup>2+</sup> levels, led to the down-regulation of MMP and ATP content. These, in turn, triggered mitochondrial dysfunction, and MAMs destabilization, and subsequent apoptosis. Additionally, the up-regulation of the protein levels of P-PERK/PERK, GRP78, ATF4, and CHOP protein expression activated the PERK-ATF4 signaling pathway, which triggered endoplasmic reticulum stress (ERS). Conversely, 1-DNJ alleviated H<sub>2</sub>O<sub>2</sub>-induced mitochondrial and MAMs dysfunction and ERS, which in turn attenuated apoptosis. Further, ATF4 knockdown inhibited MFN2 protein expression, which attenuated H<sub>2</sub>O<sub>2</sub>-induced MMP inhibition, Ca<sup>2+</sup> overload, ROS production, and mitochondrial damage. In summary, 1-DNJ mitigated OS-induced mitochondrial dysfunction in GCs and regulated ER–mitochondrial communication through MAMs, reducing OS-induced apoptosis. The present study demonstrates that 1-DNJ protects ovarian GCs from OS-induced damage by modulating ER and mitochondrial homeostasis through MAMs, offering new perspectives and a theoretical basis for the treatment of ovarian diseases. |
| format | Article |
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| spelling | doaj-art-8a5592b6ec674a3fbdf87953da530be72025-08-20T02:24:43ZengMDPI AGAntioxidants2076-39212025-04-0114445610.3390/antiox14040456Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling PathwayWenwen Xing0Mengxuan Li1Binbin Wang2Lele Huo3Wanru Tian4Fangcai Ge5Manman Shen6Liumei Sun7Jiying Liu8Shali Yu9Jiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaJiangsu Key Laboratory of Sericultural and Animal Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, ChinaDepartment of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong 226019, ChinaOxidative stress (OS) is regarded as a major contributor to granulosa cellapoptosis in ovarian disease. 1-Deoxynojirimycin (1-DNJ), a naturally occurring plant alkaloid, exhibits antioxidant, anti-inflammatory, and metabolism-modulating properties. Mitochondria and endoplasmic reticulum (ER), crucial organelles regulating oxidative balance, interact through mitochondria-associated endoplasmic reticulum membranes (MAMs) for signaling and molecular exchange. However, it remains unclear whether 1-DNJ attenuates oxidative damage in ovarian granulosa cells (GCs) via MAMs-mediated ER–mitochondria crosstalk, which needs further exploration. This study aimed to investigate the mechanisms by which 1-DNJ affects oxidative damage and apoptosis induced by OS in porcine follicular GCs by regulating mitochondrial function, MAMs, and ER interactions. Here, we found that GCs suffered from OS, accompanied by the up-regulation of ROS and MDA, alongside reduced activity of antioxidant enzymes (CAT and T-SOD). Further studies revealed that the up-regulation of MAMs proteins (MFN2, MCU, and VDAC1) and pro-apoptosis proteins (BAX and Cleaved-capase3), along with increased mitochondrial ROS and Ca<sup>2+</sup> levels, led to the down-regulation of MMP and ATP content. These, in turn, triggered mitochondrial dysfunction, and MAMs destabilization, and subsequent apoptosis. Additionally, the up-regulation of the protein levels of P-PERK/PERK, GRP78, ATF4, and CHOP protein expression activated the PERK-ATF4 signaling pathway, which triggered endoplasmic reticulum stress (ERS). Conversely, 1-DNJ alleviated H<sub>2</sub>O<sub>2</sub>-induced mitochondrial and MAMs dysfunction and ERS, which in turn attenuated apoptosis. Further, ATF4 knockdown inhibited MFN2 protein expression, which attenuated H<sub>2</sub>O<sub>2</sub>-induced MMP inhibition, Ca<sup>2+</sup> overload, ROS production, and mitochondrial damage. In summary, 1-DNJ mitigated OS-induced mitochondrial dysfunction in GCs and regulated ER–mitochondrial communication through MAMs, reducing OS-induced apoptosis. The present study demonstrates that 1-DNJ protects ovarian GCs from OS-induced damage by modulating ER and mitochondrial homeostasis through MAMs, offering new perspectives and a theoretical basis for the treatment of ovarian diseases.https://www.mdpi.com/2076-3921/14/4/456ovarian granulosa cellsoxidative stress1-DNJendoplasmic reticulum stressmitochondrial dysfunctionmitochondria-associated endoplasmic reticulum membrane |
| spellingShingle | Wenwen Xing Mengxuan Li Binbin Wang Lele Huo Wanru Tian Fangcai Ge Manman Shen Liumei Sun Jiying Liu Shali Yu Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway Antioxidants ovarian granulosa cells oxidative stress 1-DNJ endoplasmic reticulum stress mitochondrial dysfunction mitochondria-associated endoplasmic reticulum membrane |
| title | Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway |
| title_full | Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway |
| title_fullStr | Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway |
| title_full_unstemmed | Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway |
| title_short | Effect of 1-DNJ on Oxidative Stress-Induced Apoptosis in Porcine Ovarian GCs Through Modulation of the PERK-ATF4/MFN2 Signaling Pathway |
| title_sort | effect of 1 dnj on oxidative stress induced apoptosis in porcine ovarian gcs through modulation of the perk atf4 mfn2 signaling pathway |
| topic | ovarian granulosa cells oxidative stress 1-DNJ endoplasmic reticulum stress mitochondrial dysfunction mitochondria-associated endoplasmic reticulum membrane |
| url | https://www.mdpi.com/2076-3921/14/4/456 |
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