Mitochonic acid 5

Mitochonic acid 5
Clinical data
Other namesMA-5
Legal status
Legal status
  • Investigational
Identifiers
  • 4-(2,4-Difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid
CAS Number
PubChem CID
ChemSpider
ChEBI
Chemical and physical data
FormulaC18H13F2NO3
Molar mass329.303 g·mol−1
3D model (JSmol)
  • C1=CC=C2C(=C1)C(=CN2)C(CC(=O)C3=C(C=C(C=C3)F)F)C(=O)O
  • InChI=InChI=1S/C18H13F2NO3/c19-10-5-6-12(15(20)7-10)17(22)8-13(18(23)24)14-9-21-16-4-2-1-3-11(14)16/h1-7,9,13,21H,8H2,(H,23,24)
  • Key:BOKQALWNGNLTOC-UHFFFAOYSA-N

Mitochonic acid 5 (also known as MA-5) is a chemical compound derived from the plant hormone indole-3-acetic acid (IAA). It is under investigation for its ability to enhance mitochondrial function and ATP production, with potential therapeutic applications in mitochondrial diseases and related conditions.

MA-5 was identified by researchers at Tohoku University through screening of a chemical library of indole-3-acetic acid analogs. The compound was selected for its ability to increase cellular ATP levels in Hep3B human hepatocellular carcinoma cells.[1] MA-5 is a mitochondria-homing compound that binds to the mitochondrial protein mitofilin (also known as Mic60),[2] a component of the mitochondrial inner membrane organizing system (MINOS). This interaction facilitates ATP synthase oligomerization and supercomplex formation, leading to enhanced local ATP production, even under conditions where the electron transport chain is impaired.[3] It also reduces mitochondrial reactive oxygen species production, maintains mitochondrial membrane potential, and promotes protective mitophagy in various stress conditions, independent of direct antioxidant effects.[4]

MA-5 was first shown to improve the survival of fibroblasts from patients with various mitochondrial diseases (including Leigh syndrome, MELAS syndrome, Leber's hereditary optic neuropathy, and Kearns–Sayre syndrome) under oxidative stress conditions.[1] Subsequent studies demonstrated that MA-5 binds mitochondria, ameliorates damage in renal tubular cells and cardiac myocytes, protects against ischemia-reperfusion injury in kidney models, and extends lifespan in a mitochondrial disease mouse model.[4] Further preclinical research has explored its effects in models of age-related neuromuscular dysfunction, Duchenne muscular dystrophy, Parkinson's disease, age-related hearing loss,[5] alcohol-induced cardiomyopathy, peritoneal fibrosis, and neuroinflammation, where it attenuates mitochondrial Ca2+ overload, improves motor performance, reduces neuronal degeneration, and supports mitochondrial respiration.[6]

References

  1. ^ a b Suzuki T, Yamaguchi H, Kikusato M, Matsuhashi T, Matsuo A, Sato T, et al. (July 2015). "Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases". The Tohoku Journal of Experimental Medicine. 236 (3): 225–232. doi:10.1620/tjem.236.225. PMID 26118651.
  2. ^ Chaurembo AI, Xing N, Chanda F, Li Y, Zhang H, Fu L, et al. (2024). "Mitofilin in cardiovascular diseases: Insights into the pathogenesis and potential pharmacological interventions". Pharmacological Research. 203 107164. doi:10.1016/j.phrs.2024.107164. PMID 38569981.
  3. ^ Matsuhashi T, Sato T, Kanno SI, Suzuki T, Matsuo A, Oba Y, et al. (June 2017). "Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases". eBioMedicine. 20: 27–38. doi:10.1016/j.ebiom.2017.05.016. PMC 5478234. PMID 28579242.
  4. ^ a b Suzuki T, Yamaguchi H, Kikusato M, Hashizume O, Nagatoishi S, Matsuo A, et al. (July 2016). "Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage". Journal of the American Society of Nephrology. 27 (7): 1925–1932. doi:10.1681/ASN.2015060623. PMC 4926982. PMID 26609120.
  5. ^ Kouga T, Miwa T, Wei F, Sunami K, Tomizawa K (2025). "Mitochonic acid 5 mitigates age-related hearing loss progression by targeting defective 2-methylthiolation in mitochondrial transfer RNAs". Frontiers in Cellular Neuroscience. 19 1541347. doi:10.3389/fncel.2025.1541347. PMC 12009901. PMID 40260078.
  6. ^ Wu X, Seida M, Abe T, Higashitani A (August 2023). "Mitochonic acid 5 attenuates age-related neuromuscular dysfunction associated with mitochondrial Ca2+ overload in Caenorhabditis elegans". npj Aging. 9 (1) 20. doi:10.1038/s41514-023-00116-2. PMC 10394014. PMID 37528117.
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