Probing the Link between Pancratistatin and Mitochondrial Apoptosis through Changes in the Membrane Dynamics on the Nanoscale.
Probing the Link between Pancratistatin and Mitochondrial Apoptosis through Changes in the Membrane Dynamics on the Nanoscale.
复制标题
通过纳米尺度膜动力学的变化探讨胰抑素与线粒体凋亡之间的联系。
DOI：
10.1021/acs.molpharmaceut.1c00926
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发表时间：
2022
影响因子：
4.9
通讯作者：
Marquardt,Drew
中科院分区：
文献类型：
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作者：
Castillo,StuartR;Rickeard,BrettW;DiPasquale,Mitchell;Nguyen,MichaelHL;Lewis-Laurent,Aislyn;Doktorova,Milka;Kav,Batuhan;Miettinen,MarkusS;Nagao,Michihiro;Kelley,ElizabethG;Marquardt,Drew
Pancratistatin（PST）是一种天然的抗病毒生物碱，已被证明对癌细胞具有特异性，并明确靶向线粒体。PST启动细胞凋亡，同时使健康的非癌细胞毫发无损。然而，PST诱导细胞凋亡的方式仍然难以捉摸，阻碍了PST作为天然抗癌治疗剂的进展。在这里，我们使用中子自旋回波（NSE）光谱，分子动力学（MD）模拟，并支持小角散射技术，研究PST的膜动力学的影响，使用生物代表性的模型膜。我们的数据表明，PST硬化的线粒体内膜（IMM）优先与心磷脂，这将导致重新定位和释放的细胞色素。其次，PST对脂质具有有序化作用，并破坏它们在IMM内的分布，这将干扰电子传递链中活性形式蛋白质的维持和功能。这些以前未报道的发现暗示PST对线粒体凋亡的影响。
Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity toward cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent. Herein, we use neutron spin–echo (NSE) spectroscopy, molecular dynamics (MD) simulations, and supporting small angle scattering techniques to study PST’s effect on membrane dynamics using biologically representative model membranes. Our data suggests that PST stiffens the inner mitochondrial membrane (IMM) by being preferentially associated with cardiolipin, which would lead to the relocation and release of cytochromec. Second, PST has an ordering effect on the lipids and disrupts their distribution within the IMM, which would interfere with the maintenance and functionality of the active forms of proteins in the electron transport chain. These previously unreported findings implicate PST’s effect on mitochondrial apoptosis.