Journal
EBIOMEDICINE
Volume 20, Issue -, Pages 27-38Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.05.016
Keywords
MA-5; Mitochondrial disease; ATPase dimer formation; Supercomplex; GDF-15
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [26670070]
- Translational Research Network Program [B20]
- Dainippon-Sumitomo Pharm
- Daiichi-Sankyo Pharm
- DSP
- Grants-in-Aid for Scientific Research [17K00856, 16K19474, 16K12735, 26670070] Funding Source: KAKEN
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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. (C) 2017 The Authors. Published by Elsevier B.V.
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