著者

Takehiro Suzuki Hiroaki Yamaguchi Motoi Kikusato Tetsuro Matsuhashi Akihiro Matsuo Takeya Sato Yuki Oba Shun Watanabe Daichi Minaki Daisuke Saigusa Hiroko Shimbo Nobuyoshi Mori Eikan Mishima Hisato Shima Yasutoshi Akiyama Yoichi Takeuchi Akinori Yuri Koichi Kikuchi Takafumi Toyohara Chitose Suzuki Masahiro Kohzuki Jun-ichi Anzai Nariyasu Mano Shigeo Kure Teruyuki Yanagisawa Yoshihisa Tomioka Masaaki Toyomizu Sadayoshi Ito Hitoshi Osaka Ken-ichiro Hayashi Takaaki Abe

出版者

東北ジャーナル刊行会

雑誌

The Tohoku Journal of Experimental Medicine (ISSN:00408727)

巻号頁・発行日

vol.236, no.3, pp.225-232, 2015 (Released:2015-06-26)

参考文献数

27

被引用文献数

2 34

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Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber’s hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.

著者

Shun Sasaki Toru Murakami Miharu Yasumuro Ayaka Makita Yutaro Oi Yuta Hiragori Shun Watanabe Rin Kudo Noriya Hayashi Iwai Ohbayashi Munetaka Sugiyama Yui Yamashita Satoshi Naito Hitoshi Onouchi

出版者

Japanese Society for Plant Biotechnology

雑誌

Plant Biotechnology (ISSN:13424580)

巻号頁・発行日

vol.40, no.1, pp.21-30, 2023-03-25 (Released:2023-03-25)

参考文献数

36

被引用文献数

1

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Perturbations in ribosome biogenesis cause a type of cellular stress called nucleolar or ribosomal stress, which triggers adaptive responses in both animal and plant cells. The Arabidopsis ANAC082 transcription factor has been identified as a key mediator of the plant nucleolar stress response. The 5′-untranslated region (5′-UTR) of ANAC082 mRNA contains an upstream ORF (uORF) encoding an evolutionarily conserved amino acid sequence. Here, we report that this uORF mediates the upregulation of ANAC082 expression in response to nucleolar stress. When transgenic Arabidopsis plants containing a luciferase reporter gene under the control of the ANAC082 promoter and 5′-UTR were treated with reagents that induced nucleolar stress, expression of the reporter gene was enhanced in a uORF sequence-dependent manner. Additionally, we examined the effect of an endoplasmic reticulum (ER) stress-inducing reagent on reporter gene expression because the closest homolog of ANAC082 in Arabidopsis, ANAC103, is involved in the ER stress response. However, the ANAC082 uORF did not respond to ER stress. Interestingly, although ANAC103 has a uORF with an amino acid sequence similar to that of the ANAC082 uORF, the C-terminal sequence critical for regulation is not well conserved among ANAC103 homologs in Brassicaceae. Transient expression assays revealed that unlike the ANAC082 uORF, the ANAC103 uORF does not exert a sequence-dependent repressive effect. Altogether, our findings suggest that the ANAC082 uORF is important for the nucleolar stress response but not for the ER stress response, and that for this reason, the uORF sequence-dependent regulation was lost in ANAC103 during evolution.