TDP-43 stabilises the processing intermediates of mitochondrial transcripts
Abstract The 43-kDa trans-activating response region DNA-binding protein 43 (TDP-43) is a product of a causative gene for amyotrophic lateral sclerosis (ALS). Despite of accumulating evidence that mitochondrial dysfunction underlies the pathogenesis of TDP-43–related ALS, the roles of wild-type TDP-...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2017-08-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-06953-y |
| _version_ | 1818843543960027136 |
|---|---|
| author | Keiichi Izumikawa Yuko Nobe Harunori Yoshikawa Hideaki Ishikawa Yutaka Miura Hiroshi Nakayama Takashi Nonaka Masato Hasegawa Naohiro Egawa Haruhisa Inoue Kouki Nishikawa Koji Yamano Richard J. Simpson Masato Taoka Yoshio Yamauchi Toshiaki Isobe Nobuhiro Takahashi |
| author_facet | Keiichi Izumikawa Yuko Nobe Harunori Yoshikawa Hideaki Ishikawa Yutaka Miura Hiroshi Nakayama Takashi Nonaka Masato Hasegawa Naohiro Egawa Haruhisa Inoue Kouki Nishikawa Koji Yamano Richard J. Simpson Masato Taoka Yoshio Yamauchi Toshiaki Isobe Nobuhiro Takahashi |
| author_sort | Keiichi Izumikawa |
| collection | DOAJ |
| description | Abstract The 43-kDa trans-activating response region DNA-binding protein 43 (TDP-43) is a product of a causative gene for amyotrophic lateral sclerosis (ALS). Despite of accumulating evidence that mitochondrial dysfunction underlies the pathogenesis of TDP-43–related ALS, the roles of wild-type TDP-43 in mitochondria are unknown. Here, we show that the small TDP-43 population present in mitochondria binds directly to a subset of mitochondrial tRNAs and precursor RNA encoded in L-strand mtDNA. Upregulated expression of TDP-43 stabilised the processing intermediates of mitochondrial polycistronic transcripts and their products including the components of electron transport and 16S mt-rRNA, similar to the phenotype observed in cells deficient for mitochondrial RNase P. Conversely, TDP-43 deficiency reduced the population of processing intermediates and impaired mitochondrial function. We propose that TDP-43 has a novel role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts. |
| first_indexed | 2024-12-19T04:59:33Z |
| format | Article |
| id | doaj.art-9971d9fd83d945bca18af986cb1ebe25 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:59:33Z |
| publishDate | 2017-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9971d9fd83d945bca18af986cb1ebe252022-12-21T20:35:07ZengNature PortfolioScientific Reports2045-23222017-08-017111410.1038/s41598-017-06953-yTDP-43 stabilises the processing intermediates of mitochondrial transcriptsKeiichi Izumikawa0Yuko Nobe1Harunori Yoshikawa2Hideaki Ishikawa3Yutaka Miura4Hiroshi Nakayama5Takashi Nonaka6Masato Hasegawa7Naohiro Egawa8Haruhisa Inoue9Kouki Nishikawa10Koji Yamano11Richard J. Simpson12Masato Taoka13Yoshio Yamauchi14Toshiaki Isobe15Nobuhiro Takahashi16Global Innovation Research Organizations, Tokyo University of Agriculture and TechnologyCore Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)Global Innovation Research Organizations, Tokyo University of Agriculture and TechnologyGlobal Innovation Research Organizations, Tokyo University of Agriculture and TechnologyGlobal Innovation Research Organizations, Tokyo University of Agriculture and TechnologyBiomolecular Characterization Unit, RIKEN Center for Sustainable Resource ScienceDepartment of Dementia and Higher Brain Function/Dementia Research Project, Tokyo Metropolitan Institute of Medical ScienceDepartment of Dementia and Higher Brain Function/Dementia Research Project, Tokyo Metropolitan Institute of Medical ScienceCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCenter for iPS Cell Research and Application (CiRA), Kyoto UniversityCellular and Structural Physiology Institute (CeSPI), Nagoya UniversityUbiquitin project, Tokyo Metropolitan Institute of Medical SciencesGlobal Innovation Research Organizations, Tokyo University of Agriculture and TechnologyCore Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST)Global Innovation Research Organizations, Tokyo University of Agriculture and TechnologyAbstract The 43-kDa trans-activating response region DNA-binding protein 43 (TDP-43) is a product of a causative gene for amyotrophic lateral sclerosis (ALS). Despite of accumulating evidence that mitochondrial dysfunction underlies the pathogenesis of TDP-43–related ALS, the roles of wild-type TDP-43 in mitochondria are unknown. Here, we show that the small TDP-43 population present in mitochondria binds directly to a subset of mitochondrial tRNAs and precursor RNA encoded in L-strand mtDNA. Upregulated expression of TDP-43 stabilised the processing intermediates of mitochondrial polycistronic transcripts and their products including the components of electron transport and 16S mt-rRNA, similar to the phenotype observed in cells deficient for mitochondrial RNase P. Conversely, TDP-43 deficiency reduced the population of processing intermediates and impaired mitochondrial function. We propose that TDP-43 has a novel role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts.https://doi.org/10.1038/s41598-017-06953-y |
| spellingShingle | Keiichi Izumikawa Yuko Nobe Harunori Yoshikawa Hideaki Ishikawa Yutaka Miura Hiroshi Nakayama Takashi Nonaka Masato Hasegawa Naohiro Egawa Haruhisa Inoue Kouki Nishikawa Koji Yamano Richard J. Simpson Masato Taoka Yoshio Yamauchi Toshiaki Isobe Nobuhiro Takahashi TDP-43 stabilises the processing intermediates of mitochondrial transcripts Scientific Reports |
| title | TDP-43 stabilises the processing intermediates of mitochondrial transcripts |
| title_full | TDP-43 stabilises the processing intermediates of mitochondrial transcripts |
| title_fullStr | TDP-43 stabilises the processing intermediates of mitochondrial transcripts |
| title_full_unstemmed | TDP-43 stabilises the processing intermediates of mitochondrial transcripts |
| title_short | TDP-43 stabilises the processing intermediates of mitochondrial transcripts |
| title_sort | tdp 43 stabilises the processing intermediates of mitochondrial transcripts |
| url | https://doi.org/10.1038/s41598-017-06953-y |
| work_keys_str_mv | AT keiichiizumikawa tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT yukonobe tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT harunoriyoshikawa tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT hideakiishikawa tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT yutakamiura tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT hiroshinakayama tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT takashinonaka tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT masatohasegawa tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT naohiroegawa tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT haruhisainoue tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT koukinishikawa tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT kojiyamano tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT richardjsimpson tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT masatotaoka tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT yoshioyamauchi tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT toshiakiisobe tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts AT nobuhirotakahashi tdp43stabilisestheprocessingintermediatesofmitochondrialtranscripts |