TDP-43 stabilises the processing intermediates of mitochondrial transcripts

Sci Rep. 2017 Aug 9;7(1):7709. doi: 10.1038/s41598-017-06953-y.

Keiichi Izumikawa ¹ ², Yuko Nobe ² ³, Harunori Yoshikawa ¹ ² ⁴, Hideaki Ishikawa ¹ ², Yutaka Miura ¹, Hiroshi Nakayama ⁵, Takashi Nonaka ⁶, Masato Hasegawa ⁶, Naohiro Egawa ⁷, Haruhisa Inoue ⁷, Kouki Nishikawa ⁸, Koji Yamano ⁹, Richard J Simpson ¹ ¹⁰, Masato Taoka ² ³, Yoshio Yamauchi ² ³, Toshiaki Isobe ² ³, Nobuhiro Takahashi ¹¹ ¹²

Affiliations

1 Global Innovation Research Organizations, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan.
2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Sanbancho 5, Chiyoda-ku, Tokyo, 102-0075, Japan.
3 Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, 1-1 Minami-ohsawa, Hachioji, Tokyo, 192-0397, Japan.
4 Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK.
5 Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
6 Department of Dementia and Higher Brain Function/Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
7 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
8 Cellular and Structural Physiology Institute (CeSPI), Nagoya University, Nagoya, 464-8601, Japan.
9 Ubiquitin project, Tokyo Metropolitan Institute of Medical Sciences, Setagaya-ku, Tokyo, 156-8506, Japan.
10 La Trobe Institute for Molecular Science (LIMS), LIMS Building 1, Room 412 La Trobe University, Bundoora, Victoria, 3086, Australia.
11 Global Innovation Research Organizations, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo, 183-8509, Japan. ntakahas@cc.tuat.ac.jp.
12 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Sanbancho 5, Chiyoda-ku, Tokyo, 102-0075, Japan. ntakahas@cc.tuat.ac.jp.

PMID: 28794432 DOI: 10.1038/s41598-017-06953-y

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.

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