Tohoku J. Exp. Med., 2015 July, 236(3)

Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases

TAKEHIRO SUZUKI,^1,2 HIROAKI YAMAGUCHI,³ MOTOI KIKUSATO,⁴ TETSURO MATSUHASHI,⁵ AKIHIRO MATSUO,¹ TAKEYA SATO,⁶ YUKI OBA,¹ SHUN WATANABE,¹ DAICHI MINAKI,⁷ DAISUKE SAIGUSA,⁸ HIROKO SHIMBO,⁹ NOBUYOSHI MORI,¹⁰ EIKAN MISHIMA,¹ HISATO SHIMA,¹ YASUTOSHI AKIYAMA,¹ YOICHI TAKEUCHI,¹ AKINORI YURI,¹¹ KOICHI KIKUCHI,^1,12 TAKAFUMI TOYOHARA,¹ CHITOSE SUZUKI,¹ MASAHIRO KOHZUKI,¹⁰ JUN-ICHI ANZAI,⁷ NARIYASU MANO,³ SHIGEO KURE,⁵ TERUYUKI YANAGISAWA,⁶ YOSHIHISA TOMIOKA,¹¹ MASAAKI TOYOMIZU,⁴ SADAYOSHI ITO,¹ HITOSHI OSAKA,¹³ KEN-ICHIRO HAYASHI1⁴ and TAKAAKI ABE^1,12,15

¹Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
²Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
³Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi, Japan
⁴Animal Nutrition, Life Sciences, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
⁵Division of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
⁶Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
⁷Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
⁸Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
⁹Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan
¹⁰Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan
¹¹Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Miyagi, Japan
¹²Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
¹³Division of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi, Japan
¹⁴Department of Biochemistry, Okayama University of Science, Okayama, Okayama, Japan
¹⁵Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Miyagi, Japan

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.

keywords —— © 5 Tohoku University Medical Press

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 236, 225-232

Correspondence: Takaaki Abe, Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, and Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: takaabe@med.tohoku.ac.jp