Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Tetsuro Matsuhashi; Takeya Sato; Shin ichiro Kanno; Takehiro Suzuki; Akihiro Matsuo; Yuki Oba; Motoi Kikusato; Emi Ogasawara; Tai Kudo; Kosuke Suzuki; Osamu Ohara; Hiroko Shimbo; Fumika Nanto; Hiroaki Yamaguchi; Daisuke Saigusa; Yasuno Mukaiyama; Akiko Watabe; Koichi Kikuchi; Hisato Shima; Eikan Mishima; Yasutoshi Akiyama; Yoshitsugu Oikawa; H. O. Hsin-Jung; Yukako Akiyama; Chitose Suzuki; Mitsugu Uematsu; Masaki Ogata; Naonori Kumagai; Masaaki Toyomizu; Atsushi Hozawa; Nariyasu Mano; Yuji Owada; Setsuya Aiba; Teruyuki Yanagisawa; Yoshihisa Tomioka; Shigeo Kure; Sadayoshi Ito; Kazuto Nakada; Ken ichiro Hayashi; Hitoshi Osaka; Takaaki Abe

doi:10.1016/j.ebiom.2017.05.016

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Tetsuro Matsuhashi, Takeya Sato, Shin ichiro Kanno, Takehiro Suzuki, Akihiro Matsuo, Yuki Oba, Motoi Kikusato, Emi Ogasawara, Tai Kudo, Kosuke Suzuki, Osamu Ohara, Hiroko Shimbo, Fumika Nanto, Hiroaki Yamaguchi, Daisuke Saigusa, Yasuno Mukaiyama, Akiko Watabe, Koichi Kikuchi, Hisato Shima, Eikan MishimaYasutoshi Akiyama, Yoshitsugu Oikawa, H. O. Hsin-Jung, Yukako Akiyama, Chitose Suzuki, Mitsugu Uematsu, Masaki Ogata, Naonori Kumagai, Masaaki Toyomizu, Atsushi Hozawa, Nariyasu Mano, Yuji Owada, Setsuya Aiba, Teruyuki Yanagisawa, Yoshihisa Tomioka, Shigeo Kure, Sadayoshi Ito, Kazuto Nakada, Ken ichiro Hayashi, Hitoshi Osaka, Takaaki Abe

Pediatrics

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Abstract

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

Original language	English
Pages (from-to)	27-38
Number of pages	12
Journal	EBioMedicine
Volume	20
DOIs	https://doi.org/10.1016/j.ebiom.2017.05.016
Publication status	Published - 06-2017

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.ebiom.2017.05.016

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Matsuhashi, T., Sato, T., Kanno, S. I., Suzuki, T., Matsuo, A., Oba, Y., Kikusato, M., Ogasawara, E., Kudo, T., Suzuki, K., Ohara, O., Shimbo, H., Nanto, F., Yamaguchi, H., Saigusa, D., Mukaiyama, Y., Watabe, A., Kikuchi, K., Shima, H., ... Abe, T. (2017). Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases. EBioMedicine, 20, 27-38. https://doi.org/10.1016/j.ebiom.2017.05.016

@article{664a2629dc4542c89b6657f193b5ebe9,

title = "Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases",

abstract = "Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.",

author = "Tetsuro Matsuhashi and Takeya Sato and Kanno, {Shin ichiro} and Takehiro Suzuki and Akihiro Matsuo and Yuki Oba and Motoi Kikusato and Emi Ogasawara and Tai Kudo and Kosuke Suzuki and Osamu Ohara and Hiroko Shimbo and Fumika Nanto and Hiroaki Yamaguchi and Daisuke Saigusa and Yasuno Mukaiyama and Akiko Watabe and Koichi Kikuchi and Hisato Shima and Eikan Mishima and Yasutoshi Akiyama and Yoshitsugu Oikawa and Hsin-Jung, {H. O.} and Yukako Akiyama and Chitose Suzuki and Mitsugu Uematsu and Masaki Ogata and Naonori Kumagai and Masaaki Toyomizu and Atsushi Hozawa and Nariyasu Mano and Yuji Owada and Setsuya Aiba and Teruyuki Yanagisawa and Yoshihisa Tomioka and Shigeo Kure and Sadayoshi Ito and Kazuto Nakada and Hayashi, {Ken ichiro} and Hitoshi Osaka and Takaaki Abe",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = jun,

doi = "10.1016/j.ebiom.2017.05.016",

language = "English",

volume = "20",

pages = "27--38",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

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Matsuhashi, T, Sato, T, Kanno, SI, Suzuki, T, Matsuo, A, Oba, Y, Kikusato, M, Ogasawara, E, Kudo, T, Suzuki, K, Ohara, O, Shimbo, H, Nanto, F, Yamaguchi, H, Saigusa, D, Mukaiyama, Y, Watabe, A, Kikuchi, K, Shima, H, Mishima, E, Akiyama, Y, Oikawa, Y, Hsin-Jung, HO, Akiyama, Y, Suzuki, C, Uematsu, M, Ogata, M, Kumagai, N, Toyomizu, M, Hozawa, A, Mano, N, Owada, Y, Aiba, S, Yanagisawa, T, Tomioka, Y, Kure, S, Ito, S, Nakada, K, Hayashi, KI, Osaka, H & Abe, T 2017, 'Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases', EBioMedicine, vol. 20, pp. 27-38. https://doi.org/10.1016/j.ebiom.2017.05.016

TY - JOUR

T1 - Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

AU - Matsuhashi, Tetsuro

AU - Sato, Takeya

AU - Kanno, Shin ichiro

AU - Suzuki, Takehiro

AU - Matsuo, Akihiro

AU - Oba, Yuki

AU - Kikusato, Motoi

AU - Ogasawara, Emi

AU - Kudo, Tai

AU - Suzuki, Kosuke

AU - Ohara, Osamu

AU - Shimbo, Hiroko

AU - Nanto, Fumika

AU - Yamaguchi, Hiroaki

AU - Saigusa, Daisuke

AU - Mukaiyama, Yasuno

AU - Watabe, Akiko

AU - Kikuchi, Koichi

AU - Shima, Hisato

AU - Mishima, Eikan

AU - Akiyama, Yasutoshi

AU - Oikawa, Yoshitsugu

AU - Hsin-Jung, H. O.

AU - Akiyama, Yukako

AU - Suzuki, Chitose

AU - Uematsu, Mitsugu

AU - Ogata, Masaki

AU - Kumagai, Naonori

AU - Toyomizu, Masaaki

AU - Hozawa, Atsushi

AU - Mano, Nariyasu

AU - Owada, Yuji

AU - Aiba, Setsuya

AU - Yanagisawa, Teruyuki

AU - Tomioka, Yoshihisa

AU - Kure, Shigeo

AU - Ito, Sadayoshi

AU - Nakada, Kazuto

AU - Hayashi, Ken ichiro

AU - Osaka, Hitoshi

AU - Abe, Takaaki

PY - 2017/6

Y1 - 2017/6

N2 - Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

AB - Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

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UR - http://www.scopus.com/inward/citedby.url?scp=85020007376&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2017.05.016

DO - 10.1016/j.ebiom.2017.05.016

M3 - Article

C2 - 28579242

AN - SCOPUS:85020007376

SN - 2352-3964

VL - 20

SP - 27

EP - 38

JO - EBioMedicine

JF - EBioMedicine

ER -

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

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