title: Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases.
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.
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Motoi
authors.initials: M
authors.lastname: Kikusato
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsuo
authors.forename: Takeya
authors.initials: T
authors.lastname: Sato
authors.forename: Yuki
authors.initials: Y
authors.lastname: Oba
authors.forename: Shun
authors.initials: S
authors.lastname: Watanabe
authors.forename: Daichi
authors.initials: D
authors.lastname: Minaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimbo
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Mori
authors.forename: Eikan
authors.initials: E
authors.lastname: Mishima
authors.forename: Hisato
authors.initials: H
authors.lastname: Shima
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Akinori
authors.initials: A
authors.lastname: Yuri
authors.forename: Koichi
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Toyohara
authors.forename: Chitose
authors.initials: C
authors.lastname: Suzuki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kohzuki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Anzai
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tomioka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toyomizu
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D055808:Drug Discovery; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry* / Q000494:pharmacology*; D028361:Mitochondrial Diseases / Q000188:drug therapy*; D010085:Oxidative Phosphorylation; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries
chemical_list: C000605791:4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid; D007210:Indoleacetic Acids; D010654:Phenylbutyrates; D054852:Small Molecule Libraries; C030737:indoleacetic acid; D000255:Adenosine Triphosphate