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首页> 外文期刊>American Journal of Physiology >CALL FOR PAPERS Mitochondrial Dynamics and Oxidative Stress in Disease Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells
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CALL FOR PAPERS Mitochondrial Dynamics and Oxidative Stress in Disease Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells

机译：呼吁论文线粒体动态和疾病线粒体氧化应激的氧化应激介导高磷酸盐诱导的胰岛素分泌细胞的分泌缺陷和细胞凋亡

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摘要

Inorganic phosphate (P;) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, P; transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated P, concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have investigated the effect of P, on secretory function and apoptosis in INS-IE clonal (3-cells and rat pancreatic islets. Elevated extracellular P, (1—5 raM) increased the mitochondrial membrane potential (A^Fm), superoxide generation, caspase activation, and cell death. Depolarization of the A^m abolished P(-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented A^Fm hyperpolarization, superoxide generation, and cytotox-icity caused by P/. High P, also promoted the opening of the mitochondrial permeability transition (PT) pore, leading to apoptosis, which was also prevented by butylmalonate. The mitochondrial anti-oxidants mitoTEMPO or MnTBAP prevented Pr-triggered PT pore opening and cytotoxicity. Elevated extracellular P; diminished ATP synthesis, cytosolic Ca2+ oscillations, and insulin content and secretion in INS-IE cells as well as in dispersed islet cells. These parameters were restored following preincubation with mitochondrial anti-oxidants. This treatment also prevented high-P,-induced phosphory-lation of ER stress proteins. We propose that elevated extracellular P,-causes mitochondrial oxidative stress linked to mitochondrial hyperpolarization. Such stress results in reduced insulin content and defective insulin secretion and cytotoxicity. Our data explain the decreased insulin content and secretion observed under hyperphosphatemic states.
机译：无机磷酸盐（P;）在细胞信号传导和能量代谢中起重要作用。在胰岛素释放细胞中，p;传输到线粒体对ATP的产生至关重要，代谢分泌耦合的信号传导因子。然而，升高的P，浓度可在各种细胞类型中具有毒性作用。潜在的分子机制尚未理解。在这里，我们研究了P的效果，对IN-IE克隆（3细胞和大鼠胰岛胰岛肝癌中的分泌功能和细胞凋亡。升高的细胞外P，（1-5 ram）增加了线粒体膜电位（a ^ fm），超氧化物生成，胱天蛋白酶活化和细胞死亡。废除P（诱导的超氧化物产生的A ^ M的去极化。丁基甘油酯，线粒体磷酸酯转运蛋白的非选择性阻滞剂，预防了P引起的^ FM超极化，超氧化物产生和细胞毒毒素 - 冰/。高P，还促进了线粒体渗透性转变（Pt）孔的开口，导致细胞凋亡，也通过丁基甘油酸酯预防。线粒体抗氧化剂Mitotempo或MnTbap防止了PR-触发的Pt孔隙开口和细胞毒性。升高的细胞外P;在IES-IE细胞以及分散的胰岛细胞中减少ATP合成，胞质CA2 +振荡和胰岛素含量和分泌物。这些参数在Prein inch后恢复用线粒体抗氧化剂的ubation。该处理还防止了高p，诱导抗ER应激蛋白的磷酸化。我们提出升高的细胞外P，包括与线粒体超极化有关的线粒体氧化应激。这种应力导致胰岛素含量降低和缺血性胰岛素分泌和细胞毒性。我们的数据解释了在高磷脂血症状态下观察到的胰岛素含量和分泌减少。

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