Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function
Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function
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DOI：
10.1681/asn.2006080825
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发表时间：
2007-01-01
影响因子：
13.6
通讯作者：
Suthanthiran, Manikkam
中科院分区：
文献类型：
--
作者：
Thomas, Dolca A.;Stauffer, Craig;Suthanthiran, Manikkam
细胞凋亡性死亡是胰岛细胞死亡的明确途径，线粒体功能障碍是胰岛细胞凋亡的重要原因。新肽D-Arg-2‘，6’-二甲基酪氨酸-Lys-Phe-NH2(SS-31)具有靶向线粒体膜、防止神经细胞和其他类型细胞氧化损伤、优化胰岛分离和改善糖尿病患者移植后功能的假说。在这方面，SS-31很容易穿透完整的小鼠胰岛，保护线粒体极化，减少胰岛细胞凋亡，增加胰岛细胞产量。在胰岛(胰腺)供体小鼠经SS-31预处理后，以及在用于分离小鼠胰岛的试剂中添加SS-31后，胰岛分离的优化是明显的。双参数流式细胞仪分析证实，添加SS-31的体外培养上清液可减少胰岛细胞的凋亡，提高胰岛细胞的存活率。在严格的边缘胰岛细胞质量移植模型中(200只小鼠胰岛移植到同基因糖尿病小鼠的肾被膜下)，并使用来自老年小鼠的胰岛(24周)，SS-31治疗与迅速和持续的正常血糖有关，而未治疗的胰岛移植接受者仍然是糖尿病患者。我们的数据提示了一种新的策略，以优化胰岛分离，减少对多个胰腺的需求，以实现1型糖尿病受者的胰岛素独立。由于SS-31对“扩大的”胰岛捐赠者有效，推测抗氧化剂SS-31可能有助于增加符合条件的器官捐赠者的数量。
Apoptotic cell death is a defined pathway for islet cell demise, and mitochondrial dysfunction contributes to islet cell apoptosis. The hypothesis that the novel peptide D-Arg-2', 6'-dimethyltyrosine-Lys-Phe-NH2 (SS-31), previously shown to target inner mitochondrial membrane and prevent oxidative damage of neuronal cells and other cell types, optimizes pancreatic islet isolation and improves posttransplantation function in recipients with diabetes was investigated. Herein is demonstrated that SS-31 readily penetrates intact mouse islets, preserves mitochondrial polarization, reduces islet cell apoptosis, and increases islet cell yield. Optimization of islet isolation is demonstrable after SS-31 pretreatment of islet (pancreas) donor mice and with the addition of SS-31 to reagents that are used in the isolation of mouse islets. The supplementation of in vitro culture medium with SS-31 reduced islet cell apoptosis and increased the viability of human islets, as ascertained by dual-parameter flow cytometry analysis. In a stringent marginal islet cell mass transplantation model (200 mouse islets transplanted under the renal capsule of syngeneic diabetic mice) and using islets that were derived from old mice (> 24 wk), SS-31 treatment was associated with prompt and sustained normoglycemia, whereas the untreated islet graft recipients remained diabetic. Our data suggest a novel strategy to optimize islet isolation and reduce the need for multiple pancreata to achieve insulin independence in the recipient with type 1 diabetes. Because SS-31 was effective with "extended" islet donors, it is hypothesized that the antioxidant SS-31 may serve to increase the pool of eligible organ donors.