Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis
Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724000491 |
| _version_ | 1797300340469530624 |
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| author | Peng Tian Zhongyan Xu Jiarong Guo Jingsong Zhao Weina Chen Wenxin Huang Manli Wang Chenyang Mi Ying Zhang Yang Yang Huidong Zhang |
| author_facet | Peng Tian Zhongyan Xu Jiarong Guo Jingsong Zhao Weina Chen Wenxin Huang Manli Wang Chenyang Mi Ying Zhang Yang Yang Huidong Zhang |
| author_sort | Peng Tian |
| collection | DOAJ |
| description | Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might induce trophoblast cell ferroptosis and then induce miscarriage, as well as regulated by a lncRNA, was completely unknown. In this work, we discovered at the first time that hypoxia could result in ferroptosis of human trophoblast cells and then induce miscarriage. We also identified a novel lncRNA (lnc-HZ06) that simultaneously regulated hypoxia (indicated by HIF1α protein), ferroptosis, and miscarriage. In mechanism, HIF1α-SUMO, instead of HIF1α itself, primarily acted as a transcription factor to promote the transcription of NCOA4 (ferroptosis indicator) in hypoxic trophoblast cells. Lnc-HZ06 promoted the SUMOylation of HIF1α by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acted as a transcription factor to promote lnc-HZ06 transcription. Thus, both lnc-HZ06 and HIF1α-SUMO formed a positive auto-regulatory feedback loop. This loop was up-regulated in hypoxic trophoblast cells, in RM villous tissues, and in placental tissues of hypoxia-treated mice, which further induced ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Furthermore, knockdown of either murine lnc-hz06 or Ncoa4 could efficiently suppress ferroptosis and alleviate miscarriage in hypoxic mouse model. Taken together, this study provided new insights in understanding the regulatory roles of lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, ferroptosis, and miscarriage, and also offered an effective approach for treatment against miscarriage. |
| first_indexed | 2024-03-07T23:05:50Z |
| format | Article |
| id | doaj.art-2b768bbbcab74f4980c3bef6f5b151ea |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-07T23:05:50Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-2b768bbbcab74f4980c3bef6f5b151ea2024-02-22T04:52:26ZengElsevierRedox Biology2213-23172024-04-0170103073Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axisPeng Tian0Zhongyan Xu1Jiarong Guo2Jingsong Zhao3Weina Chen4Wenxin Huang5Manli Wang6Chenyang Mi7Ying Zhang8Yang Yang9Huidong Zhang10Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, 610041, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, 610041, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, 610041, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, ChinaResearch Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China; Corresponding author.Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might induce trophoblast cell ferroptosis and then induce miscarriage, as well as regulated by a lncRNA, was completely unknown. In this work, we discovered at the first time that hypoxia could result in ferroptosis of human trophoblast cells and then induce miscarriage. We also identified a novel lncRNA (lnc-HZ06) that simultaneously regulated hypoxia (indicated by HIF1α protein), ferroptosis, and miscarriage. In mechanism, HIF1α-SUMO, instead of HIF1α itself, primarily acted as a transcription factor to promote the transcription of NCOA4 (ferroptosis indicator) in hypoxic trophoblast cells. Lnc-HZ06 promoted the SUMOylation of HIF1α by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acted as a transcription factor to promote lnc-HZ06 transcription. Thus, both lnc-HZ06 and HIF1α-SUMO formed a positive auto-regulatory feedback loop. This loop was up-regulated in hypoxic trophoblast cells, in RM villous tissues, and in placental tissues of hypoxia-treated mice, which further induced ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Furthermore, knockdown of either murine lnc-hz06 or Ncoa4 could efficiently suppress ferroptosis and alleviate miscarriage in hypoxic mouse model. Taken together, this study provided new insights in understanding the regulatory roles of lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, ferroptosis, and miscarriage, and also offered an effective approach for treatment against miscarriage.http://www.sciencedirect.com/science/article/pii/S2213231724000491LncRNA or lnc-HZ06Trophoblast cell ferroptosisHypoxiaRecurrent miscarriageSUMOylated HIF1α and NCOA4 |
| spellingShingle | Peng Tian Zhongyan Xu Jiarong Guo Jingsong Zhao Weina Chen Wenxin Huang Manli Wang Chenyang Mi Ying Zhang Yang Yang Huidong Zhang Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis Redox Biology LncRNA or lnc-HZ06 Trophoblast cell ferroptosis Hypoxia Recurrent miscarriage SUMOylated HIF1α and NCOA4 |
| title | Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis |
| title_full | Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis |
| title_fullStr | Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis |
| title_full_unstemmed | Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis |
| title_short | Hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc-HZ06/HIF1α-SUMO/NCOA4 axis |
| title_sort | hypoxia causes trophoblast cell ferroptosis to induce miscarriage through lnc hz06 hif1α sumo ncoa4 axis |
| topic | LncRNA or lnc-HZ06 Trophoblast cell ferroptosis Hypoxia Recurrent miscarriage SUMOylated HIF1α and NCOA4 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724000491 |
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