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Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases
Tetsuro Matsuhashi1, Takeya Sato2, Shin-Ichiro Kanno3
1Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
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.
Insights
Mitochonic acid MA-5 shows promise for treating mitochondrial diseases. This therapeutic drug effectively increased ATP, protected cells, and reduced oxidative stress in most patient-derived cells.
Area of Science:
- Biochemistry
- Cell Biology
- Mitochondrial Medicine
Background:
- Mitochondrial dysfunction is implicated in numerous diseases, causing oxidative stress and ATP depletion.
- Current therapies targeting mitochondrial biogenesis and oxidative stress have shown limited clinical success.
- Mitochonic acid MA-5 is a novel therapeutic agent investigated for mitochondrial disorders.
Purpose of the Study:
- To evaluate the efficacy of MA-5 in fibroblasts from patients with diverse genetic mitochondrial diseases.
- To elucidate the ATP-producing mechanisms and cell-protective effects of MA-5.
- To assess the impact of MA-5 on oxidative stress markers like GDF-15.
Main Methods:
- Collected fibroblasts from 25 patients with various genetic mitochondrial mutations.
- Assessed MA-5's cell protective effects and ATP production.
- Measured GDF-15 levels under oxidative stress and in a disease model (Mitomouse).
- Investigated MA-5's effects on mitochondrial structure, ATP synthase, and supercomplex formation.
Main Results:
- MA-5 demonstrated a significant response in 96% of patient fibroblasts (24/25).
- MA-5 abrogated the oxidative stress-induced increase in GDF-15 and reduced elevated serum GDF-15 in Mitomouse.
- MA-5 enhanced mitochondrial ATP production and reduced reactive oxygen species (ROS) by facilitating ATP synthase oligomerization and supercomplex formation, independent of the electron transport chain (ETC).
- MA-5 mitigated mitochondrial fragmentation and restored mitochondrial cristae structure and dynamics.
Conclusions:
- MA-5 exhibits broad potential as a therapeutic drug for various mitochondrial diseases.
- MA-5 facilitates mitochondrial ATP production and reduces ROS through novel mechanisms involving ATP synthase.
- GDF-15 may serve as a useful biomarker for monitoring treatment response in future MA-5 clinical trials.
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