TDP-43 stabilises the processing intermediates of mitochondrial transcripts

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

doi:10.1038/s41598-017-06953-y

TDP-43 stabilises the processing intermediates of mitochondrial transcripts

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 (Lead / Corresponding author)

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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.

Original language	English
Article number	7709
Pages (from-to)	1-14
Number of pages	14
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-06953-y
Publication status	Published - 9 Aug 2017

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Izumikawa, K., Nobe, Y., Yoshikawa, H., Ishikawa, H., Miura, Y., Nakayama, H., Nonaka, T., Hasegawa, M., Egawa, N., Inoue, H., Nishikawa, K., Yamano, K., Simpson, R. J., Taoka, M., Yamauchi, Y., Isobe, T., & Takahashi, N. (2017). TDP-43 stabilises the processing intermediates of mitochondrial transcripts. Scientific Reports, 7, 1-14. Article 7709. https://doi.org/10.1038/s41598-017-06953-y

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title = "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-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.",

keywords = "Journal article",

author = "Keiichi Izumikawa and Yuko Nobe and Harunori Yoshikawa and Hideaki Ishikawa and Yutaka Miura and Hiroshi Nakayama and Takashi Nonaka and Masato Hasegawa and Naohiro Egawa and Haruhisa Inoue and Kouki Nishikawa and Koji Yamano and Simpson, {Richard J.} and Masato Taoka and Yoshio Yamauchi and Toshiaki Isobe and Nobuhiro Takahashi",

note = "This work was funded by grants from the Core Research for Evolutional Science and Technology Program of the Japan Science and Technology Agency (JPMJCR13M2, to T.I., H.N. and N.T.), by a promotional grant and a grant for human resource development (24241075, to N.T.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Global Innovation Research Organization of Tokyo University of Agriculture & Technology.",

year = "2017",

month = aug,

day = "9",

doi = "10.1038/s41598-017-06953-y",

language = "English",

volume = "7",

pages = "1--14",

journal = "Scientific Reports",

issn = "2045-2322",

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Izumikawa, K, Nobe, Y, Yoshikawa, H, Ishikawa, H, Miura, Y, Nakayama, H, Nonaka, T, Hasegawa, M, Egawa, N, Inoue, H, Nishikawa, K, Yamano, K, Simpson, RJ, Taoka, M, Yamauchi, Y, Isobe, T & Takahashi, N 2017, 'TDP-43 stabilises the processing intermediates of mitochondrial transcripts', Scientific Reports, vol. 7, 7709, pp. 1-14. https://doi.org/10.1038/s41598-017-06953-y

TY - JOUR

T1 - TDP-43 stabilises the processing intermediates of mitochondrial transcripts

AU - Izumikawa, Keiichi

AU - Nobe, Yuko

AU - Yoshikawa, Harunori

AU - Ishikawa, Hideaki

AU - Miura, Yutaka

AU - Nakayama, Hiroshi

AU - Nonaka, Takashi

AU - Hasegawa, Masato

AU - Egawa, Naohiro

AU - Inoue, Haruhisa

AU - Nishikawa, Kouki

AU - Yamano, Koji

AU - Simpson, Richard J.

AU - Taoka, Masato

AU - Yamauchi, Yoshio

AU - Isobe, Toshiaki

AU - Takahashi, Nobuhiro

N1 - This work was funded by grants from the Core Research for Evolutional Science and Technology Program of the Japan Science and Technology Agency (JPMJCR13M2, to T.I., H.N. and N.T.), by a promotional grant and a grant for human resource development (24241075, to N.T.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Global Innovation Research Organization of Tokyo University of Agriculture & Technology.

PY - 2017/8/9

Y1 - 2017/8/9

N2 - 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.

AB - 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.

KW - Journal article

U2 - 10.1038/s41598-017-06953-y

DO - 10.1038/s41598-017-06953-y

M3 - Article

C2 - 28794432

SN - 2045-2322

VL - 7

SP - 1

EP - 14

JO - Scientific Reports

JF - Scientific Reports

M1 - 7709

ER -

TDP-43 stabilises the processing intermediates of mitochondrial transcripts

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