Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice
Mitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inh...
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| Format: | Article |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.788512/full |
| _version_ | 1818844309567307776 |
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| author | Yuanyuan Li Ning-Hua Mei Gui-Ping Cheng Jing Yang Li-Quan Zhou |
| author_facet | Yuanyuan Li Ning-Hua Mei Gui-Ping Cheng Jing Yang Li-Quan Zhou |
| author_sort | Yuanyuan Li |
| collection | DOAJ |
| description | Mitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inhibition of DRP1 activity by mitochondrial division inhibitor-1, a small molecule reported to specifically inhibit DRP1 activity, can cause severe developmental arrest of preimplantation embryos in a dose-dependent manner in mice. Meanwhile, DRP1 inhibition resulted in mitochondrial dysfunction including decreased mitochondrial activity, loss of mitochondrial membrane potential, reduced mitochondrial copy number and inadequate ATP by disrupting both expression and activity of DRP1 and mitochondrial complex assembly, leading to excessive ROS production, severe DNA damage and cell cycle arrest at 2-cell embryo stage. Furthermore, reduced transcriptional and translational activity and altered histone modifications in DRP1-inhibited embryos contributed to impeded zygotic genome activation, which prevented early embryos from efficient development beyond 2-cell embryo stage. These results show that DRP1 inhibition has potential cytotoxic effects on mammalian reproduction, and DRP1 inhibitor should be used with caution when it is applied to treat diseases. Additionally, this study improves our understanding of the crosstalk between mitochondrial metabolism and zygotic genome activation. |
| first_indexed | 2024-12-19T05:11:43Z |
| format | Article |
| id | doaj.art-ef194160a06c460a917680c8670c1c4d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-19T05:11:43Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-ef194160a06c460a917680c8670c1c4d2022-12-21T20:34:47ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-12-01910.3389/fcell.2021.788512788512Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in MiceYuanyuan Li0Ning-Hua Mei1Gui-Ping Cheng2Jing Yang3Li-Quan Zhou4Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaReproductive Medical Center, Renmin Hospital, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan University, Wuhan, ChinaInstitute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaReproductive Medical Center, Renmin Hospital, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan University, Wuhan, ChinaInstitute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaMitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inhibition of DRP1 activity by mitochondrial division inhibitor-1, a small molecule reported to specifically inhibit DRP1 activity, can cause severe developmental arrest of preimplantation embryos in a dose-dependent manner in mice. Meanwhile, DRP1 inhibition resulted in mitochondrial dysfunction including decreased mitochondrial activity, loss of mitochondrial membrane potential, reduced mitochondrial copy number and inadequate ATP by disrupting both expression and activity of DRP1 and mitochondrial complex assembly, leading to excessive ROS production, severe DNA damage and cell cycle arrest at 2-cell embryo stage. Furthermore, reduced transcriptional and translational activity and altered histone modifications in DRP1-inhibited embryos contributed to impeded zygotic genome activation, which prevented early embryos from efficient development beyond 2-cell embryo stage. These results show that DRP1 inhibition has potential cytotoxic effects on mammalian reproduction, and DRP1 inhibitor should be used with caution when it is applied to treat diseases. Additionally, this study improves our understanding of the crosstalk between mitochondrial metabolism and zygotic genome activation.https://www.frontiersin.org/articles/10.3389/fcell.2021.788512/fullmitochondrial dysfunctionpreimplantation developmentzygotic genome activationROSDRP1 |
| spellingShingle | Yuanyuan Li Ning-Hua Mei Gui-Ping Cheng Jing Yang Li-Quan Zhou Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice Frontiers in Cell and Developmental Biology mitochondrial dysfunction preimplantation development zygotic genome activation ROS DRP1 |
| title | Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice |
| title_full | Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice |
| title_fullStr | Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice |
| title_full_unstemmed | Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice |
| title_short | Inhibition of DRP1 Impedes Zygotic Genome Activation and Preimplantation Development in Mice |
| title_sort | inhibition of drp1 impedes zygotic genome activation and preimplantation development in mice |
| topic | mitochondrial dysfunction preimplantation development zygotic genome activation ROS DRP1 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.788512/full |
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