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

EBioMedicine. 2017 Jun;20:27-38. doi: 10.1016/j.ebiom.2017.05.016. Epub 2017 May 13.


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.

Keywords: ATPase dimer formation; GDF-15; MA-5; Mitochondrial disease; Supercomplex.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Biomarkers
  • Cell Line
  • Cell Survival / drug effects
  • DNA, Mitochondrial
  • Disease Models, Animal
  • Fibroblast Growth Factors / metabolism
  • Fibroblasts / metabolism
  • Growth Differentiation Factor 15 / metabolism
  • Humans
  • Indoleacetic Acids / pharmacology*
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / drug therapy
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Proton-Translocating ATPases / chemistry
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Multiprotein Complexes / metabolism
  • Mutation
  • Organelle Biogenesis
  • Phenylbutyrates / pharmacology*
  • Prognosis
  • Protective Agents
  • Protein Binding
  • Protein Multimerization / drug effects*


  • 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid
  • Biomarkers
  • DNA, Mitochondrial
  • Growth Differentiation Factor 15
  • Indoleacetic Acids
  • Multiprotein Complexes
  • Phenylbutyrates
  • Protective Agents
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases