TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response.
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclea...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-05-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1007947 |
| _version_ | 1818589578536157184 |
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| author | Peng Wang Jianwen Deng Jie Dong Jianghong Liu Eileen H Bigio Marsel Mesulam Tao Wang Lei Sun Li Wang Alan Yueh-Luen Lee Warren A McGee Xiaoping Chen Kazuo Fushimi Li Zhu Jane Y Wu |
| author_facet | Peng Wang Jianwen Deng Jie Dong Jianghong Liu Eileen H Bigio Marsel Mesulam Tao Wang Lei Sun Li Wang Alan Yueh-Luen Lee Warren A McGee Xiaoping Chen Kazuo Fushimi Li Zhu Jane Y Wu |
| author_sort | Peng Wang |
| collection | DOAJ |
| description | Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases. |
| first_indexed | 2024-12-16T09:42:53Z |
| format | Article |
| id | doaj.art-cb1fbfa3c5db486d80e3a3d979127886 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-16T09:42:53Z |
| publishDate | 2019-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-cb1fbfa3c5db486d80e3a3d9791278862022-12-21T22:36:13ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-05-01155e100794710.1371/journal.pgen.1007947TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response.Peng WangJianwen DengJie DongJianghong LiuEileen H BigioMarsel MesulamTao WangLei SunLi WangAlan Yueh-Luen LeeWarren A McGeeXiaoping ChenKazuo FushimiLi ZhuJane Y WuMutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.https://doi.org/10.1371/journal.pgen.1007947 |
| spellingShingle | Peng Wang Jianwen Deng Jie Dong Jianghong Liu Eileen H Bigio Marsel Mesulam Tao Wang Lei Sun Li Wang Alan Yueh-Luen Lee Warren A McGee Xiaoping Chen Kazuo Fushimi Li Zhu Jane Y Wu TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genetics |
| title | TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. |
| title_full | TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. |
| title_fullStr | TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. |
| title_full_unstemmed | TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. |
| title_short | TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. |
| title_sort | tdp 43 induces mitochondrial damage and activates the mitochondrial unfolded protein response |
| url | https://doi.org/10.1371/journal.pgen.1007947 |
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