The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation
Recent studies demonstrate that lipid peroxidation-induced ferroptosis participates in 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-evoked neurotoxicity and cognitive dysfunction. Melatonin has been indicated to confer neuroprotection against brain diseases via its potent anti-ferroptotic effects. Th...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Ecotoxicology and Environmental Safety |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S014765132401618X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823856950736060416 |
|---|---|
| author | Quan Yuan Mingwei Wang Zhaoxiang Zhang Ruofei Wang Dechao Wang Zichun Sang Pu Zhao Xiaoli Liu Xiaoying Zhu Gaofeng Liang Hua Fan Dongmei Wang |
| author_facet | Quan Yuan Mingwei Wang Zhaoxiang Zhang Ruofei Wang Dechao Wang Zichun Sang Pu Zhao Xiaoli Liu Xiaoying Zhu Gaofeng Liang Hua Fan Dongmei Wang |
| author_sort | Quan Yuan |
| collection | DOAJ |
| description | Recent studies demonstrate that lipid peroxidation-induced ferroptosis participates in 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-evoked neurotoxicity and cognitive dysfunction. Melatonin has been indicated to confer neuroprotection against brain diseases via its potent anti-ferroptotic effects. Therefore, this study aims to explore whether melatonin can mitigate BDE-47-elicited cognitive impairment via suppressing ferroptosis, and further delineate the underlying mechanisms. Our results found that melatonin administration effectively inhibited BDE-47-induced ferroptosis in mice hippocampi and murine hippocampal neuronal HT-22 cells. Acyl-CoA synthetase long-chain family member 4 (ACSL4), a key lipid metabolism enzyme dictating ferroptosis sensitivity, accompanied by higher MDA and lipid reactive oxygen species (ROS), was remarkably increased under BDE-47 stress, while melatonin supplementation could suppress the elevated ACSL4 in vivo and in vitro. Furthermore, melatonin facilitated lysosomal ACSL4 degradation through enhancing lysosome-associated membrane protein type 2a (LAMP2a) expression and chaperone-mediated autophagy (CMA) activity, while LAMP2a knockdown abrogated the positive effects of melatonin on ACSL4 elimination in BDE-47-treated HT-22 cells. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) activation by melatonin contributed to LAMP2a upregulation and CMA of ACSL4 and subsequent neuronal ferroptosis. Importantly, melatonin, CMA activator CA77.1, and ACSL4 inhibitor rosiglitazone (RSG) administration substantially attenuated neuronal/synaptic injury and cognitive deficits following BDE-47 exposure. Taken together, these findings revealed that melatonin could prevent BDE-47-provoked ferroptosis in the hippocampal neurons and mitigate cognitive dysfunction by facilitating ACSL4 degradation via Nrf2-chaperone-mediated autophagy. Therefore, melatonin might be a potential candidate for treating BDE-47-elicited neurotoxicity and neurobehavioral disorder. |
| format | Article |
| id | doaj-art-f84b6e07db1c4440ba95d9b139672f57 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-f84b6e07db1c4440ba95d9b139672f572025-02-12T05:29:36ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01290117542The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradationQuan Yuan0Mingwei Wang1Zhaoxiang Zhang2Ruofei Wang3Dechao Wang4Zichun Sang5Pu Zhao6Xiaoli Liu7Xiaoying Zhu8Gaofeng Liang9Hua Fan10Dongmei Wang11Henan Province Rongkang Hospital, Luoyang, ChinaThe Affiliated Hospital of Hangzhou Normal University, Hangzhou, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, ChinaThe First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China; Correspondence to: The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, Henan 471003, ChinaCollege of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China; Correspondence to: College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, Henan 471003, ChinaRecent studies demonstrate that lipid peroxidation-induced ferroptosis participates in 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47)-evoked neurotoxicity and cognitive dysfunction. Melatonin has been indicated to confer neuroprotection against brain diseases via its potent anti-ferroptotic effects. Therefore, this study aims to explore whether melatonin can mitigate BDE-47-elicited cognitive impairment via suppressing ferroptosis, and further delineate the underlying mechanisms. Our results found that melatonin administration effectively inhibited BDE-47-induced ferroptosis in mice hippocampi and murine hippocampal neuronal HT-22 cells. Acyl-CoA synthetase long-chain family member 4 (ACSL4), a key lipid metabolism enzyme dictating ferroptosis sensitivity, accompanied by higher MDA and lipid reactive oxygen species (ROS), was remarkably increased under BDE-47 stress, while melatonin supplementation could suppress the elevated ACSL4 in vivo and in vitro. Furthermore, melatonin facilitated lysosomal ACSL4 degradation through enhancing lysosome-associated membrane protein type 2a (LAMP2a) expression and chaperone-mediated autophagy (CMA) activity, while LAMP2a knockdown abrogated the positive effects of melatonin on ACSL4 elimination in BDE-47-treated HT-22 cells. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) activation by melatonin contributed to LAMP2a upregulation and CMA of ACSL4 and subsequent neuronal ferroptosis. Importantly, melatonin, CMA activator CA77.1, and ACSL4 inhibitor rosiglitazone (RSG) administration substantially attenuated neuronal/synaptic injury and cognitive deficits following BDE-47 exposure. Taken together, these findings revealed that melatonin could prevent BDE-47-provoked ferroptosis in the hippocampal neurons and mitigate cognitive dysfunction by facilitating ACSL4 degradation via Nrf2-chaperone-mediated autophagy. Therefore, melatonin might be a potential candidate for treating BDE-47-elicited neurotoxicity and neurobehavioral disorder.http://www.sciencedirect.com/science/article/pii/S014765132401618XBDE-47MelatoninChaperone-mediated autophagyFerroptosisACSL4Cognitive impairment |
| spellingShingle | Quan Yuan Mingwei Wang Zhaoxiang Zhang Ruofei Wang Dechao Wang Zichun Sang Pu Zhao Xiaoli Liu Xiaoying Zhu Gaofeng Liang Hua Fan Dongmei Wang The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation Ecotoxicology and Environmental Safety BDE-47 Melatonin Chaperone-mediated autophagy Ferroptosis ACSL4 Cognitive impairment |
| title | The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation |
| title_full | The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation |
| title_fullStr | The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation |
| title_full_unstemmed | The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation |
| title_short | The ameliorative effects of melatonin against BDE-47-induced hippocampal neuronal ferroptosis and cognitive dysfunction through Nrf2-Chaperone-mediated autophagy of ACSL4 degradation |
| title_sort | ameliorative effects of melatonin against bde 47 induced hippocampal neuronal ferroptosis and cognitive dysfunction through nrf2 chaperone mediated autophagy of acsl4 degradation |
| topic | BDE-47 Melatonin Chaperone-mediated autophagy Ferroptosis ACSL4 Cognitive impairment |
| url | http://www.sciencedirect.com/science/article/pii/S014765132401618X |
| work_keys_str_mv | AT quanyuan theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT mingweiwang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT zhaoxiangzhang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT ruofeiwang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT dechaowang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT zichunsang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT puzhao theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT xiaoliliu theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT xiaoyingzhu theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT gaofengliang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT huafan theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT dongmeiwang theameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT quanyuan ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT mingweiwang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT zhaoxiangzhang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT ruofeiwang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT dechaowang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT zichunsang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT puzhao ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT xiaoliliu ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT xiaoyingzhu ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT gaofengliang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT huafan ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation AT dongmeiwang ameliorativeeffectsofmelatoninagainstbde47inducedhippocampalneuronalferroptosisandcognitivedysfunctionthroughnrf2chaperonemediatedautophagyofacsl4degradation |