Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1
Objectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment.Methods: Cognitive func...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-03-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.832707/full |
| _version_ | 1811273082324647936 |
|---|---|
| author | Yan Hu Yan Hu Yile Zhou Yajie Yang Haihong Tang Yuan Si Zhouyi Chen Yi Shi Yi Shi Hao Fang |
| author_facet | Yan Hu Yan Hu Yile Zhou Yajie Yang Haihong Tang Yuan Si Zhouyi Chen Yi Shi Yi Shi Hao Fang |
| author_sort | Yan Hu |
| collection | DOAJ |
| description | Objectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment.Methods: Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals.Results: Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice.Conclusion: Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment. |
| first_indexed | 2024-04-12T22:51:40Z |
| format | Article |
| id | doaj.art-c9219edb3ab14a978d0af1e704f74ca2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T22:51:40Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c9219edb3ab14a978d0af1e704f74ca22022-12-22T03:13:19ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-03-011310.3389/fphar.2022.832707832707Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1Yan Hu0Yan Hu1Yile Zhou2Yajie Yang3Haihong Tang4Yuan Si5Zhouyi Chen6Yi Shi7Yi Shi8Hao Fang9Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Jinshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Jinshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Jinshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, ChinaInstitute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, ChinaShanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, ChinaDepartment of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, ChinaObjectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment.Methods: Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals.Results: Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice.Conclusion: Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment.https://www.frontiersin.org/articles/10.3389/fphar.2022.832707/fulldiabetescognitive dysfunctionmitochondrial fissiondynamin-related protein 1reactive oxidative stressapoptosis |
| spellingShingle | Yan Hu Yan Hu Yile Zhou Yajie Yang Haihong Tang Yuan Si Zhouyi Chen Yi Shi Yi Shi Hao Fang Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1 Frontiers in Pharmacology diabetes cognitive dysfunction mitochondrial fission dynamin-related protein 1 reactive oxidative stress apoptosis |
| title | Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1 |
| title_full | Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1 |
| title_fullStr | Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1 |
| title_full_unstemmed | Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1 |
| title_short | Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1 |
| title_sort | metformin protects against diabetes induced cognitive dysfunction by inhibiting mitochondrial fission protein drp1 |
| topic | diabetes cognitive dysfunction mitochondrial fission dynamin-related protein 1 reactive oxidative stress apoptosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.832707/full |
| work_keys_str_mv | AT yanhu metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT yanhu metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT yilezhou metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT yajieyang metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT haihongtang metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT yuansi metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT zhouyichen metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT yishi metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT yishi metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 AT haofang metforminprotectsagainstdiabetesinducedcognitivedysfunctionbyinhibitingmitochondrialfissionproteindrp1 |