Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus
Abstract Dynamin-related protein 1 (Drp1)-mediated mitochondrial dysfunction is associated with synaptic injury in the diabetic brain. However, the dysfunctional mitochondria by Drp1 deletion in the diabetic brain are poorly understood. Here, we investigated the effects of neuron-specific Drp1 delet...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03723-7 |
| _version_ | 1819298483789627392 |
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| author | Gyeongah Park Jong Youl Lee Hye Min Han Hyeong Seok An Zhen Jin Eun Ae Jeong Kyung Eun Kim Hyun Joo Shin Jaewoong Lee Dawon Kang Hyun Joon Kim Yong Chul Bae Gu Seob Roh |
| author_facet | Gyeongah Park Jong Youl Lee Hye Min Han Hyeong Seok An Zhen Jin Eun Ae Jeong Kyung Eun Kim Hyun Joo Shin Jaewoong Lee Dawon Kang Hyun Joon Kim Yong Chul Bae Gu Seob Roh |
| author_sort | Gyeongah Park |
| collection | DOAJ |
| description | Abstract Dynamin-related protein 1 (Drp1)-mediated mitochondrial dysfunction is associated with synaptic injury in the diabetic brain. However, the dysfunctional mitochondria by Drp1 deletion in the diabetic brain are poorly understood. Here, we investigated the effects of neuron-specific Drp1 deletion on synaptic damage and mitophagy in the hippocampus of a high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. HFD/STZ-induced diabetic mice exhibited metabolic disturbances and synaptic damages. Floxed Drp1 mice were crossed with Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα)-Cre mice, to generate neuron-specific Drp1 knockout (Drp1cKO) mice, which showed marked mitochondrial swelling and dendritic spine loss in hippocampal neurons. In particular, diabetic Drp1cKO mice exhibited an increase in dendritic spine loss and higher levels of oxidative stress and neuroinflammation compared with diabetic wild-type (WT) mice. Diabetic WT mice generally displayed increased Drp1-induced small mitochondrial morphology in hippocampal neurons, but large mitochondria were prominently observed in diabetic Drp1cKO mice. The levels of microtubule-associated protein 1 light-chain 3 and lysosomal-associated membrane protein 1 proteins were significantly increased in the hippocampus of diabetic Drp1cKO mice compared with diabetic WT mice. The inhibition of Drp1 adversely promotes synaptic injury and neurodegeneration in the diabetic brain. The findings suggest that the exploratory mechanisms behind Drp1-mediated mitochondrial dysfunction could provide a possible therapeutic target for diabetic brain complications. |
| first_indexed | 2024-12-24T05:30:37Z |
| format | Article |
| id | doaj.art-8cf0aa66bfca4fb98b592bd13a8bcbd7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-24T05:30:37Z |
| publishDate | 2021-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-8cf0aa66bfca4fb98b592bd13a8bcbd72022-12-21T17:13:11ZengNature Publishing GroupCell Death and Disease2041-48892021-05-0112511510.1038/s41419-021-03723-7Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampusGyeongah Park0Jong Youl Lee1Hye Min Han2Hyeong Seok An3Zhen Jin4Eun Ae Jeong5Kyung Eun Kim6Hyun Joo Shin7Jaewoong Lee8Dawon Kang9Hyun Joon Kim10Yong Chul Bae11Gu Seob Roh12Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Neurobiology, School of Dentistry, Kyungpook National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityBio Anti-Aging Medical Research Center, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityDepartment of Anatomy and Neurobiology, School of Dentistry, Kyungpook National UniversityDepartment of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National UniversityAbstract Dynamin-related protein 1 (Drp1)-mediated mitochondrial dysfunction is associated with synaptic injury in the diabetic brain. However, the dysfunctional mitochondria by Drp1 deletion in the diabetic brain are poorly understood. Here, we investigated the effects of neuron-specific Drp1 deletion on synaptic damage and mitophagy in the hippocampus of a high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. HFD/STZ-induced diabetic mice exhibited metabolic disturbances and synaptic damages. Floxed Drp1 mice were crossed with Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα)-Cre mice, to generate neuron-specific Drp1 knockout (Drp1cKO) mice, which showed marked mitochondrial swelling and dendritic spine loss in hippocampal neurons. In particular, diabetic Drp1cKO mice exhibited an increase in dendritic spine loss and higher levels of oxidative stress and neuroinflammation compared with diabetic wild-type (WT) mice. Diabetic WT mice generally displayed increased Drp1-induced small mitochondrial morphology in hippocampal neurons, but large mitochondria were prominently observed in diabetic Drp1cKO mice. The levels of microtubule-associated protein 1 light-chain 3 and lysosomal-associated membrane protein 1 proteins were significantly increased in the hippocampus of diabetic Drp1cKO mice compared with diabetic WT mice. The inhibition of Drp1 adversely promotes synaptic injury and neurodegeneration in the diabetic brain. The findings suggest that the exploratory mechanisms behind Drp1-mediated mitochondrial dysfunction could provide a possible therapeutic target for diabetic brain complications.https://doi.org/10.1038/s41419-021-03723-7 |
| spellingShingle | Gyeongah Park Jong Youl Lee Hye Min Han Hyeong Seok An Zhen Jin Eun Ae Jeong Kyung Eun Kim Hyun Joo Shin Jaewoong Lee Dawon Kang Hyun Joon Kim Yong Chul Bae Gu Seob Roh Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus Cell Death and Disease |
| title | Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus |
| title_full | Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus |
| title_fullStr | Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus |
| title_full_unstemmed | Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus |
| title_short | Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus |
| title_sort | ablation of dynamin related protein 1 promotes diabetes induced synaptic injury in the hippocampus |
| url | https://doi.org/10.1038/s41419-021-03723-7 |
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