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Mitochonic acid 5 (MA-5) Sale

(Synonyms: MA-5) 目录号 : GC31123

An inhibitor of mitochondrial dysfunction

Mitochonic acid 5 (MA-5) Chemical Structure

Cas No.:1354707-41-7

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10mM (in 1mL DMSO)
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实验参考方法

Cell experiment:

The mouse BV-2 cells used in this study are cultured in L-DMEM supplemented with 10% fetal bovine serum (FBS) at 37°C in an atmosphere with 5% CO2. To induce inflammatory injury, cells are treated with 10 ng/mL TNFα for about 12 h. Mitochonic acid 5 (0-10 μM) is incubated with BV-2 cells for about 12 h with TNFα treatment[2].

Animal experiment:

Mice[1]For evaluation of the blood concentrations of Mitochonic acid 5 (MA-5), Mitochonic acid 5 is orally administered at doses of 25, 50, or 150 mg/kg to C57/BL 6 mice, and blood samples are collected at the designated times. After 1 hour, the mice are euthanized. The blood concentration of Mitochonic acid 5 is determined by LC/MS/MS[1].

References:

[1]. Suzuki T, et al. Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage. J Am Soc Nephrol. 2016 Jul;27(7):1925-32.
[2]. Lei Q, et al. Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFα-induced apoptosis via increased Bnip3-related mitophagy. Cell Mol Biol Lett. 2018 Apr 5;23:14.

产品描述

Mitochonic acid 5 is an inhibitor of mitochondrial dysfunction.1 It increases intracellular ATP levels in Hep3B cells when used at a concentration of 3 ?M. Mitochonic acid 5 (5 ?M) rescues LPS-induced apoptosis and decreases in the mitochondrial membrane potential in BV-2 microglial cells.2 It protects against decreases in cell viability induced by L-buthionine-(S,R)-sulfoximine in fibroblasts isolated from patients with various mitochondrial diseases, including Leigh syndrome and Leber’s hereditary optic neuropathy (EC50s = 2.3-5.1 ?M), in an electron transport chain-independent manner.1 Mitochonic acid 5 (50 mg/kg) reduces plasma levels of creatinine and decreases acute renal tubular necrosis in a mouse model of bilateral retroperitoneal renal ischemia-reperfusion injury.3

1.Suzuki, T., Yamaguchi, H., Kikusato, M., et al.Mitochonic acid 5 (MA-5), a derivative of the plant hormone indole-3-acetic acid, improves survival of fibroblasts from patients with mitochondrial diseasesTohoku J. Exp. Med.236(3)225-232(2015) 2.Tan, J., Chen, S.-X., Lei, Q.-Y., et al.Mitochonic acid 5 regulates mitofusin 2 to protect microgliaNeural Regen. Res.16(9)1813-1820(2021) 3.Suzuki, T., Yamaguchi, H., Kikusato, M., et al.Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damageJ. Am. Soc. Nephrol.27(7)1925-1932(2016)

Chemical Properties

Cas No. 1354707-41-7 SDF
别名 MA-5
Canonical SMILES O=C(O)C(CC(C1=CC=C(F)C=C1F)=O)C2=CNC3=C2C=CC=C3
分子式 C18H13F2NO3 分子量 329.3
溶解度 DMSO : ≥ 106.66 mg/mL (323.90 mM) 储存条件 Store at -20°C
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1 mM 3.0367 mL 15.1837 mL 30.3674 mL
5 mM 0.6073 mL 3.0367 mL 6.0735 mL
10 mM 0.3037 mL 1.5184 mL 3.0367 mL
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Research Update

Mitochonic acid-5 ameliorates chlorhexidine gluconate-induced peritoneal fibrosis in mice

Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis, attributable to inflammation and mitochondrial dysfunction. Mitochonic acid-5 (MA-5), an indole-3-acetic acid derivative, improves mitochondrial dysfunction and has therapeutic potential against various diseases including kidney diseases. However, whether MA-5 is effective against peritoneal fibrosis remains unclear. Therefore, we investigated the effect of MA-5 using a peritoneal fibrosis mouse model. Peritoneal fibrosis was induced in C57BL/6 mice via intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 3 weeks. MA-5 was administered daily by oral gavage. The mice were divided into control, MA-5, CG, and CG + MA-5 groups. Following treatment, immunohistochemical analyses were performed. Fibrotic thickening of the parietal peritoneum induced by CG was substantially attenuated by MA-5. The number of α-smooth muscle actin-positive myofibroblasts, transforming growth factor β-positive cells, F4/80-positive macrophages, monocyte chemotactic protein 1-positive cells, and 4-hydroxy-2-nonenal-positive cells was considerably decreased. In addition, reduced ATP5a1-positive and uncoupling protein 2-positive cells in the CG group were notably increased by MA-5. MA-5 may ameliorate peritoneal fibrosis by suppressing macrophage infiltration and oxidative stress, thus restoring mitochondrial function. Overall, MA-5 has therapeutic potential against peritoneal fibrosis.

Mitochonic acid 5 ameliorates the motor deficits in the MPTP-induced mouse Parkinson's disease model by AMPK-mediated autophagy

Parkinson's disease (PD) is a well-known neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, and oxidative stress and neuroinflammation are also associated with the pathogenesis of PD. Mitochonic acid 5 (MA-5), an analogue of indole-3-acetic acid, exerts key protective roles in inhibiting apoptosis, oxidative stress and neuroinflammation in multiple diseases. However, whether MA-5 can be beneficial for PD remains unclear. Hence, the aim of this study was to investigate the neuroprotective role of MA-5 in PD. In the current study, MPTP-challenged mice were treated as the in vivo model, and the effect of MA-5 on the motor function, neuronal survival, oxidative stress, neuroinflammation and the underlying mechanisms involved with AMPK and autophagy were determined. We revealed that MA-5 obviously up-regulated the phosphorylation of AMPK and promoted the autophagy (indicated by the increased LC3II/LC3I, parkin, pink and decreased p62) in substantia nigra (SN), ameliorated the motor deficits, up-regulated the expression of TH, suppressed the inflammation (indicated by the decreased protein levels of interleukin (IL)-1b, IL-6, tumour necrosis factor a) in SN in MPTP-induced mice. However, these patterns were reversed after the treatment of Compound C, an inhibitor of AMPK; also, after the application of CSA, an inhibitor of autophagy, MA-5 cannot play against the neurotoxicity of MPTP in mice. These combined results suggest that MA-5 can protect against MPTP-induced neurotoxicity to ameliorate the impaired motor function, which may be modulated via activation of AMPK-induced autophagy.

Mitochonic acid 5 regulates mitofusin 2 to protect microglia

Microglial apoptosis is associated with neuroinflammation and no effective strategies are currently available to protect microglia against inflammation-induced apoptosis. Mouse microglial BV-2 cells (5 × 106) were incubated with 10 μg/mL lipopolysaccharides for 12 hours to mimic an inflammatory environment. Then the cells were co-cultured with mitochonic acid 5 (MA-5) for another 12 hours. MA-5 improved the survival of lipopolysaccharide-exposed cells. MA-5 decreased the activity of caspase-3, which is associated with apoptosis. MA-5 reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells, and increased adenosine triphosphate levels in cells. MA-5 decreased the open state of the mitochondrial permeability transition pore and reduced calcium overload and diffusion of second mitochondria-derived activator of caspase (Smac). MA-5 decreased the expression of apoptosis-related proteins (mitochondrial Smac, cytoplasmic Smac, pro-caspase-3, cleaved-caspase-3, and caspase-9), and increased the levels of anti-apoptotic proteins (Bcl2 and X-linked inhibitor of apoptosis protein), mitochondria-related proteins (mitochondrial fusion protein 2, mitochondrial microtubule-associated proteins 1A/1B light chain 3B II), and autophagy-related proteins (Beclin1, p62 and autophagy related 5). However, MA-5 did not promote mitochondrial homeostasis or decrease microglial apoptosis when Mitofusin 2 expression was silenced. This shows that MA-5 increased Mitofusin 2-related mitophagy, reversed cellular energy production and maintained energy metabolism in BV-2 cells in response to lipopolysaccharide-induced inflammation. These findings indicate that MA-5 may promote the survival of microglial cells via Mitofusin 2-related mitophagy in response to lipopolysaccharide-induced inflammation.

Mitochonic Acid 5 Improves Duchenne Muscular Dystrophy and Parkinson's Disease Model of Caenorhabditis elegans

Mitochonic Acid 5 (MA-5) enhances mitochondrial ATP production, restores fibroblasts from mitochondrial disease patients and extends the lifespan of the disease model "Mitomouse". Additionally, MA-5 interacts with mitofilin and modulates the mitochondrial inner membrane organizing system (MINOS) in mammalian cultured cells. Here, we used the nematode Caenorhabditis elegans to investigate whether MA-5 improves the Duchenne muscular dystrophy (DMD) model. Firstly, we confirmed the efficient penetration of MA-5 in the mitochondria of C. elegans. MA-5 also alleviated symptoms such as movement decline, muscular tone, mitochondrial fragmentation and Ca2+ accumulation of the DMD model. To assess the effect of MA-5 on mitochondria perturbation, we employed a low concentration of rotenone with or without MA-5. MA-5 significantly suppressed rotenone-induced mitochondria reactive oxygen species (ROS) increase, mitochondrial network fragmentation and nuclear destruction in body wall muscles as well as endogenous ATP levels decline. In addition, MA-5 suppressed rotenone-induced degeneration of dopaminergic cephalic (CEP) neurons seen in the Parkinson's disease (PD) model. Furthermore, the application of MA-5 reduced mitochondrial swelling due to the immt-1 null mutation. These results indicate that MA-5 has broad mitochondrial homing and MINOS stabilizing activity in metazoans and may be a therapeutic agent for these by ameliorating mitochondrial dysfunction in DMD and PD.

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

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.