SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes
Abstract Background Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-d...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04246-9 |
| _version_ | 1797773955605463040 |
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| author | Yanmin Chang Cailin Wang Jiahui Zhu Siyi Zheng Shangqi Sun Yanqing Wu Xingjun Jiang Lulu Li Rong Ma Gang Li |
| author_facet | Yanmin Chang Cailin Wang Jiahui Zhu Siyi Zheng Shangqi Sun Yanqing Wu Xingjun Jiang Lulu Li Rong Ma Gang Li |
| author_sort | Yanmin Chang |
| collection | DOAJ |
| description | Abstract Background Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown. Methods Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1–GRP75–IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs. Results Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1–GRP75–IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions. Conclusions In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients. |
| first_indexed | 2024-03-12T22:13:44Z |
| format | Article |
| id | doaj.art-6a3f34e842954b2196905366f244745c |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-12T22:13:44Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-6a3f34e842954b2196905366f244745c2023-07-23T11:25:28ZengBMCJournal of Translational Medicine1479-58762023-07-0121111610.1186/s12967-023-04246-9SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranesYanmin Chang0Cailin Wang1Jiahui Zhu2Siyi Zheng3Shangqi Sun4Yanqing Wu5Xingjun Jiang6Lulu Li7Rong Ma8Gang Li9Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown. Methods Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1–GRP75–IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs. Results Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1–GRP75–IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions. Conclusions In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.https://doi.org/10.1186/s12967-023-04246-9Diabetes-associated cognitive dysfunctionSirtuin3Mitochondria-associated ER membranesVDAC1–GRP75–IP3R complexHonokiol |
| spellingShingle | Yanmin Chang Cailin Wang Jiahui Zhu Siyi Zheng Shangqi Sun Yanqing Wu Xingjun Jiang Lulu Li Rong Ma Gang Li SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes Journal of Translational Medicine Diabetes-associated cognitive dysfunction Sirtuin3 Mitochondria-associated ER membranes VDAC1–GRP75–IP3R complex Honokiol |
| title | SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes |
| title_full | SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes |
| title_fullStr | SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes |
| title_full_unstemmed | SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes |
| title_short | SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes |
| title_sort | sirt3 ameliorates diabetes associated cognitive dysfunction via regulating mitochondria associated er membranes |
| topic | Diabetes-associated cognitive dysfunction Sirtuin3 Mitochondria-associated ER membranes VDAC1–GRP75–IP3R complex Honokiol |
| url | https://doi.org/10.1186/s12967-023-04246-9 |
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