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

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  • Suzuki Takehiro
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine Renal Division, Brigham and Women’s Hospital and Harvard Medical School
  • Yamaguchi Hiroaki
    Department of Pharmaceutical Sciences, Tohoku University Hospital
  • Kikusato Motoi
    Animal Nutrition, Life Sciences, Graduate School of Agricultural Science, Tohoku University
  • Matsuhashi Tetsuro
    Division of Pediatrics, Tohoku University Graduate School of Medicine
  • Matsuo Akihiro
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Sato Takeya
    Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine
  • Oba Yuki
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Watanabe Shun
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Minaki Daichi
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Saigusa Daisuke
    Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University
  • Shimbo Hiroko
    Clinical Research Institute, Kanagawa Children’s Medical Center
  • Mori Nobuyoshi
    Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine Sendai
  • Mishima Eikan
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Shima Hisato
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Akiyama Yasutoshi
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Takeuchi Yoichi
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Yuri Akinori
    Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences
  • Kikuchi Koichi
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine
  • Toyohara Takafumi
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Suzuki Chitose
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Kohzuki Masahiro
    Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine Sendai
  • Anzai Jun-ichi
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Mano Nariyasu
    Department of Pharmaceutical Sciences, Tohoku University Hospital
  • Kure Shigeo
    Division of Pediatrics, Tohoku University Graduate School of Medicine
  • Yanagisawa Teruyuki
    Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine
  • Tomioka Yoshihisa
    Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences
  • Toyomizu Masaaki
    Animal Nutrition, Life Sciences, Graduate School of Agricultural Science, Tohoku University
  • Ito Sadayoshi
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine
  • Osaka Hitoshi
    Division of Pediatrics, Jichi Medical University
  • Hayashi Ken-ichiro
    Department of Biochemistry, Okayama University of Science
  • Abe Takaaki
    Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering

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  • Validity of the Special Needs Education Assessment Tool (SNEAT), a Newly Developed Scale for Children with Disabilities
  • a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases

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Abstract

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.

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