- 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
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.