High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast
Abstract Background p66Shc, as a redox enzyme, regulates reactive oxygen species (ROS) production in mitochondria and autophagy. However, the mechanisms by which p66Shc affects autophagosome formation are not fully understood. Methods p66Shc expression and its location in the trophoblast cells were...
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01621-x |
| _version_ | 1797199247934750720 |
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| author | Lulu Ji Xiaoli Zhang Zhiguo Chen Yuexiao Wang Hengxuan Zhu Yaru Nai Yanyi Huang Rujie Lai Yu Zhong Xiting Yang Qiongtao Wang Hanyang Hu Lin Wang |
| author_facet | Lulu Ji Xiaoli Zhang Zhiguo Chen Yuexiao Wang Hengxuan Zhu Yaru Nai Yanyi Huang Rujie Lai Yu Zhong Xiting Yang Qiongtao Wang Hanyang Hu Lin Wang |
| author_sort | Lulu Ji |
| collection | DOAJ |
| description | Abstract Background p66Shc, as a redox enzyme, regulates reactive oxygen species (ROS) production in mitochondria and autophagy. However, the mechanisms by which p66Shc affects autophagosome formation are not fully understood. Methods p66Shc expression and its location in the trophoblast cells were detected in vivo and in vitro. Small hairpin RNAs or CRISPR/Cas9, RNA sequencing, and confocal laser scanning microscope were used to clarify p66Shc’s role in regulating autophagic flux and STING activation. In addition, p66Shc affects mitochondrial-associated endoplasmic reticulum membranes (MAMs) formation were observed by transmission electron microscopy (TEM). Mitochondrial function was evaluated by detected cytoplastic mitochondrial DNA (mtDNA) and mitochondrial membrane potential (MMP). Results High glucose induces the expression and mitochondrial translocation of p66Shc, which promotes MAMs formation and stimulates PINK1-PRKN-mediated mitophagy. Moreover, mitochondrial localized p66Shc reduces MMP and triggers cytosolic mtDNA release, thus activates cGAS/STING signaling and ultimately leads to enhanced autophagy and cellular senescence. Specially, we found p66Shc is required for the interaction between STING and LC3II, as well as between STING and ATG5, thereby regulates cGAS/STING-mediated autophagy. We also identified hundreds of genes associated several biological processes including aging are co-regulated by p66Shc and ATG5, deletion either of which results in diminished cellular senescence. Conclusion p66Shc is not only implicated in the initiation of autophagy by promoting MAMs formation, but also helps stabilizing active autophagic flux by activating cGAS/STING pathway in trophoblast. |
| first_indexed | 2024-04-24T07:12:44Z |
| format | Article |
| id | doaj.art-355dc557b67546e9957a01dcd9c6838a |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-04-24T07:12:44Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-355dc557b67546e9957a01dcd9c6838a2024-04-21T11:25:15ZengBMCCell Communication and Signaling1478-811X2024-04-0122111510.1186/s12964-024-01621-xHigh glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblastLulu Ji0Xiaoli Zhang1Zhiguo Chen2Yuexiao Wang3Hengxuan Zhu4Yaru Nai5Yanyi Huang6Rujie Lai7Yu Zhong8Xiting Yang9Qiongtao Wang10Hanyang Hu11Lin Wang12Department of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Ultrasound in Gynecology and Obstetrics, Zhongnan Hospital of Wuhan UniversityDepartment of Human Anatomy, Basic Medical Sciences of Xinxiang Medical UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityDepartment of Histology and Embryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan UniversityAbstract Background p66Shc, as a redox enzyme, regulates reactive oxygen species (ROS) production in mitochondria and autophagy. However, the mechanisms by which p66Shc affects autophagosome formation are not fully understood. Methods p66Shc expression and its location in the trophoblast cells were detected in vivo and in vitro. Small hairpin RNAs or CRISPR/Cas9, RNA sequencing, and confocal laser scanning microscope were used to clarify p66Shc’s role in regulating autophagic flux and STING activation. In addition, p66Shc affects mitochondrial-associated endoplasmic reticulum membranes (MAMs) formation were observed by transmission electron microscopy (TEM). Mitochondrial function was evaluated by detected cytoplastic mitochondrial DNA (mtDNA) and mitochondrial membrane potential (MMP). Results High glucose induces the expression and mitochondrial translocation of p66Shc, which promotes MAMs formation and stimulates PINK1-PRKN-mediated mitophagy. Moreover, mitochondrial localized p66Shc reduces MMP and triggers cytosolic mtDNA release, thus activates cGAS/STING signaling and ultimately leads to enhanced autophagy and cellular senescence. Specially, we found p66Shc is required for the interaction between STING and LC3II, as well as between STING and ATG5, thereby regulates cGAS/STING-mediated autophagy. We also identified hundreds of genes associated several biological processes including aging are co-regulated by p66Shc and ATG5, deletion either of which results in diminished cellular senescence. Conclusion p66Shc is not only implicated in the initiation of autophagy by promoting MAMs formation, but also helps stabilizing active autophagic flux by activating cGAS/STING pathway in trophoblast.https://doi.org/10.1186/s12964-024-01621-xHigh glucosep66ShcAutophagycGAS/STINGMAM |
| spellingShingle | Lulu Ji Xiaoli Zhang Zhiguo Chen Yuexiao Wang Hengxuan Zhu Yaru Nai Yanyi Huang Rujie Lai Yu Zhong Xiting Yang Qiongtao Wang Hanyang Hu Lin Wang High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast Cell Communication and Signaling High glucose p66Shc Autophagy cGAS/STING MAM |
| title | High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast |
| title_full | High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast |
| title_fullStr | High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast |
| title_full_unstemmed | High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast |
| title_short | High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast |
| title_sort | high glucose induced p66shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast |
| topic | High glucose p66Shc Autophagy cGAS/STING MAM |
| url | https://doi.org/10.1186/s12964-024-01621-x |
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