ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials
Abstract Background As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell–cell communication that plays a crucial role in pathology and physiology. How...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Particle and Fibre Toxicology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12989-024-00562-0 |
| _version_ | 1797350192147595264 |
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| author | Xinpei Lin Wei Wang Xiangyu Chang Cheng Chen Zhenkun Guo Guangxia Yu Wenya Shao Siying Wu Qunwei Zhang Fuli Zheng Huangyuan Li |
| author_facet | Xinpei Lin Wei Wang Xiangyu Chang Cheng Chen Zhenkun Guo Guangxia Yu Wenya Shao Siying Wu Qunwei Zhang Fuli Zheng Huangyuan Li |
| author_sort | Xinpei Lin |
| collection | DOAJ |
| description | Abstract Background As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell–cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiO2NPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation. Results After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation. Conclusion Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity. Graphical abstract |
| first_indexed | 2024-03-08T12:41:12Z |
| format | Article |
| id | doaj.art-43897ee5bd56444b9c05bf2efba7e0d0 |
| institution | Directory Open Access Journal |
| issn | 1743-8977 |
| language | English |
| last_indexed | 2024-03-08T12:41:12Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Particle and Fibre Toxicology |
| spelling | doaj.art-43897ee5bd56444b9c05bf2efba7e0d02024-01-21T12:07:26ZengBMCParticle and Fibre Toxicology1743-89772024-01-0121112010.1186/s12989-024-00562-0ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterialsXinpei Lin0Wei Wang1Xiangyu Chang2Cheng Chen3Zhenkun Guo4Guangxia Yu5Wenya Shao6Siying Wu7Qunwei Zhang8Fuli Zheng9Huangyuan Li10Department of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityThe Key Laboratory of Environment and Health, School of Public Health, Fujian Medical UniversityDepartment of Epidemiology and Population Health, School of Public Health and Information Sciences, University of LouisvilleDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityDepartment of Preventive Medicine, School of Public Health, Fujian Medical UniversityAbstract Background As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell–cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiO2NPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation. Results After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation. Conclusion Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity. Graphical abstracthttps://doi.org/10.1186/s12989-024-00562-0Cobalt nanoparticlesTitanium dioxide nanoparticlesMulti-walled carbon nanotubesTunneling nanotubesROSmtROS |
| spellingShingle | Xinpei Lin Wei Wang Xiangyu Chang Cheng Chen Zhenkun Guo Guangxia Yu Wenya Shao Siying Wu Qunwei Zhang Fuli Zheng Huangyuan Li ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials Particle and Fibre Toxicology Cobalt nanoparticles Titanium dioxide nanoparticles Multi-walled carbon nanotubes Tunneling nanotubes ROS mtROS |
| title | ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials |
| title_full | ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials |
| title_fullStr | ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials |
| title_full_unstemmed | ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials |
| title_short | ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials |
| title_sort | ros mtros promotes tnts formation via the pi3k akt mtor pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials |
| topic | Cobalt nanoparticles Titanium dioxide nanoparticles Multi-walled carbon nanotubes Tunneling nanotubes ROS mtROS |
| url | https://doi.org/10.1186/s12989-024-00562-0 |
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