Background
Elamipretide (MTP-131), as a water-soluble tetrapeptide, can enhance cellular ATP synthesis to improve electron transport and reduce the formation of ROS. And it inhibits lipid peroxidation and prevents mitochondrial swelling, aiding in mitochondrial protection[1][2].
In vitro experiment it exhibited that treatment with 1 μM elamipretide in cultured ARPE-19 cells results in accelerating an increase in mitochondrial volume[3]. In vitro, added in the freeze media with 1 and 10 μM Elamipretide obviously improved post-thaw sperm parameters including motility and viability, stability of the plasma membrane, and mitochondria and chromosomes[4]. In control INS1 cells, treatment with 1 μM Elamipretide for 20 h suffiently increase the engulfment of mitochondria into autophagosomes, but it has no increase at 10 μM Elamipretide, suggesting a complete reversal of mitochondrial fragmentation induced by nutrient excess at 10 μM, while not being complete at 1 μM[5].
In vivo, 1 mg/kg MTP-131 treatment reversed visual decline without improving glycemic control or reducing bodyweight in diabetic mouse models[6]. In vivo test it shown that treatment repeatly with 5 mg/kg elamipretide intraperitoneally in mice provided maximum neuroprotective effects without any adverse effects[7]. Moreover, treatment with 3 mg/kg/day SS-31 (elamipretide) restored redox homeostasis, improved mitochondrial quality, and increased exercise tolerance without an increase in mitochondrial content in aged mice[8].
Dai DF, et al. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 6:1067-1076.
Zhao K, et al., 2005. Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines. Biochem Pharma. 70:1796-1806.
Grosser JA, et al. The effects of a mitochondrial targeted peptide (elamipretide/SS31) on BAX recruitment and activation during apoptosis. BMC Res Notes. 2021 May 22;14(1):198.
Bai H, et al. Elamipretide as a potential candidate for relieving cryodamage to human spermatozoa during cryopreservation. Cryobiology. 2020 Aug;95:138-142.
Petcherski A, et al. Elamipretide Promotes Mitophagosome Formation and Prevents Its Reduction Induced by Nutrient Excess in INS1 β-cells. J Mol Biol. 2018 Dec 7;430(24):4823-4833.
Alam NM, et al. A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. Dis Model Mech. 2015 Jul 1;8(7):701-10.
Zhao W, et al. Elamipretide (SS-31) improves mitochondrial dysfunction, synaptic and memory impairment induced by lipopolysaccharide in mice. J Neuroinflammation. 2019 Nov 20;16(1):230.
Campbell MD, et al. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radic Biol Med. 2019 Apr;134:268-281.
参考文献:
Elamipretide (MTP-131) 作为一种水溶性四肽，可以增强细胞 ATP 合成，从而改善电子传输并减少 ROS 的形成。并抑制脂质过氧化，防止线粒体肿胀，有助于保护线粒体[1][2]。
体外实验表明， 1 µ；培养的 ARPE-19 细胞中的 M elamipretide 导致线粒体体积加速增加[3]。在体外，在冷冻培养基中添加 1 和 10 μM Elamipretide 显着改善了解冻后的精子参数，包括运动性和活力、质膜稳定性以及线粒体和染色体[4]。在对照 INS1 细胞中，用 1 77777#181;M Elamipretide 处理 20 小时足以增加线粒体被自噬体吞噬，但在 10 μM Elamipretide 时没有增加，表明在 10 &88188881 时营养过剩诱导的线粒体断裂完全逆转;M，虽然在 1 µ 处未完成；M[5]。
在体内，1 mg/kg MTP-131 治疗可逆转视力下降，但不会改善血糖控制或减少糖尿病小鼠模型的体重[6]。体内试验表明，在小鼠腹腔内重复使用 5 mg/kg elamipretide 进行治疗可提供最大的神经保护作用，且无任何不良反应[7]。此外，用 3 mg/kg/天的 SS-31（elamipretide）治疗可恢复氧化还原稳态、改善线粒体质量并增加运动耐量，而不会增加老年小鼠的线粒体含量[8]。
Dai DF, et al.压力过载引起的心力衰竭的全球蛋白质组学和通路分析及其通过线粒体靶向肽的衰减。 Circ 心脏衰竭。 6:1067-1076。
Zhao K, et al., 2005. 线粒体靶向肽可防止神经元细胞系中叔丁基氢过氧化物诱导的线粒体去极化和细胞凋亡。生化制药。 70:1796-1806。
Grosser JA 等。线粒体靶向肽 (elamipretide/SS31) 对细胞凋亡过程中 BAX 募集和激活的影响。 BMC Res 注释。 2021 年 5 月 22 日；14(1):198。
Bai H, et al. Elamipretide 作为减轻低温保存过程中对人类精子的低温损伤的潜在候选药物。低温生物学。 2020 年 8 月；95:138-142。
Petcherski A 等人。 Elamipretide 在 INS1 β-细胞中促进线粒体吞噬体形成并防止其因营养过剩而减少。 J Mol Biol。 2018 年 12 月 7 日；430(24):4823-4833。
Alam NM 等。线粒体疗法可逆转糖尿病小鼠模型的视力下降。 Dis 模型机械。 2015 年 7 月 1 日；8(7):701-10。
赵伟等。 Elamipretide (SS-31) 改善小鼠中由脂多糖诱导的线粒体功能障碍、突触和记忆障碍。 J 神经炎症。 2019 年 11 月 20 日；16(1):230。
坎贝尔医学博士等。用 SS-31 改善线粒体功能可逆转与年龄相关的氧化还原应激并提高老年小鼠的运动耐量。自由基生物学医学。 2019 年 4 月；134:268-281。
Protocol
| Cell experiment [1]: |
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Cell lines
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RGC-5 cells
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Preparation Method
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MTP-131 pretreatment and induction of oxidative stress RGC-5 cells were seeded at a density of 1×104 cells/well in 6-well plates and incubated in 5% CO2 at 37°C for 24 h. Cells at approximately 70% confluence were pretreated with 0.01, 0.1 or 1 μM MTP-131 in serum-free DMEM at 37°C for 1 h and then rinsed twice with PBS. Then, RGC-5 cells were exposed to 500 μM H2O2 in serum-free DMEM for 24 h to induce a sustained oxidative stress in vitro.
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Reaction Conditions
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0.01, 0.1 or 1 μM; at 37°C for 1 h
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Applications
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Pretreatment of cells with MTP-131 inhibited H2O2-induced cytotoxicity and reduced LDH release in a dose-dependent manner, compared with cells treated with H2O2 alone. Mitochondrial depolarization and ROS generation were also prevented by MTP-131 pretreatment. In addition, MTP-131 pretreatment inhibited cytochrome c release from mitochondria to cytoplasm, and significantly reduced apoptosis in RGC-5 cells, compared with cells treated with H2O2 alone.
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| Animal experiment [2]: |
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Animal models
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Dogs
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Preparation Method
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14 dogs with microembolization-induced HF (heart failure) were randomized to 3 months monotherapy with subcutaneous injections of elamipretide (0.5 mg/kg once daily, HF+ELA, n=7) or saline (Control, HF-CON, n=7). LV ejection fraction (EF), plasma n-terminal pro-brain natriuretic peptide (nt-pro BNP), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) were measured before (pre-treatment) and 3 months after initiating therapy (post-treatment). MITO respiration, membrane potential (δψm), maximum rate of ATP synthesis and ATP/ADP ratio were measured in isolated LV cardiomyocytes obtained at post-treatment.
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Dosage form
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0.5 mg/kg once daily; s.c.
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Applications
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Long-term therapy with elamipretide improves LV systolic function, normalizes plasma biomarkers and reverses MITO abnormalities in LV myocardium of dogs with advanced HF.
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参考文献:
[1]Chen M, et al. Protective effect of mitochondria?targeted peptide MTP?131 against oxidative stress?induced apoptosis in RGC?5 cells. Mol Med Rep. 2017 Apr;15(4):2179-2185.
[2]Sabbah HN, et al. Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure. Circ Heart Fail. 2016 Feb;9(2):e002206.
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