TDP-43 stabilises the processing intermediates of mitochondrial transcripts PMID: 28794432

ADC Targets in Oncology

2026-04-10

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. [email protected].
12. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Sanbancho 5, Chiyoda-ku, Tokyo, 102-0075, Japan. [email protected].

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.