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

作者：Matsuhashi Tetsuro; Sato Takeya; Kanno Shin ichiro; Suzuki Takehiro; Matsuo Akihiro; Oba Yuki; Kikusato Motoi; Ogasawara Emi; Kudo Tai; Suzuki Kosuke; Ohara Osamu; Shimbo Hiroko; Nanto Fumika; Yamaguchi Hiroaki; Saigusa Daisuke; Mukaiyama Yasuno; Watabe Akiko; Kikuchi Koichi; Shima Hisato; Mishima Eikan; Akiyama Yasutoshi; Oikawa Yoshitsugu; Ho Hsin Jung; Akiyama Yukako; Suzuki Chitose; Uematsu Mitsugu; Ogata Masaki; Kumagai Naonori; Toyomizu Masaaki

来源：EBioMedicine, 2017, 20: 27-38.

DOI：10.1016/j.ebiom.2017.05.016

• MA-5
• Mitochondrial disease
• ATPase dimer formation
• Supercomplex
• GDF-15

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.

• 出版日期2017-6