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-...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9971d9fd83d945bca18af986cb1ebe25
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spelling	oai:doaj.org-article:9971d9fd83d945bca18af986cb1ebe252021-12-02T12:31:54ZTDP-43 stabilises the processing intermediates of mitochondrial transcripts10.1038/s41598-017-06953-y2045-2322https://doaj.org/article/9971d9fd83d945bca18af986cb1ebe252017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06953-yhttps://doaj.org/toc/2045-2322Abstract 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.Keiichi IzumikawaYuko NobeHarunori YoshikawaHideaki IshikawaYutaka MiuraHiroshi NakayamaTakashi NonakaMasato HasegawaNaohiro EgawaHaruhisa InoueKouki NishikawaKoji YamanoRichard J. SimpsonMasato TaokaYoshio YamauchiToshiaki IsobeNobuhiro TakahashiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	TDP-43 stabilises the processing intermediates of mitochondrial transcripts
title_short	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_sort	tdp-43 stabilises the processing intermediates of mitochondrial transcripts
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9971d9fd83d945bca18af986cb1ebe25
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_version_	1718394230596960256

TDP-43 stabilises the processing intermediates of mitochondrial transcripts

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