线粒体特异性肽两亲物诱导线粒体功能障碍和外周T细胞淋巴瘤（PTCL）损伤。

Mitochondria-specific peptide amphiphiles induce mitochondrial dysfunction and peripheral T-cell lymphomas (PTCL) damage.

作者信息

Sun Qi, Gui Ailing, Zou Aihua, Yan Yichen, Qiu Shi, Zhu Shun, Liu Wen, Zuo Ji, Zhang Qunling, Yang Ling

机构信息

Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.

College of Chemistry and Materials Science, Shanghai Normal University, Shanghai, China.

出版信息

Ann Transl Med. 2022 May;10(10):570. doi: 10.21037/atm-22-2233.

DOI:10.21037/atm-22-2233

PMID:35722364

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9201132/

Abstract

BACKGROUND

Peripheral T-cell lymphomas (PTCL) are aggressive lymphomas with poor prognosis, and therefore, there is a pressing need to explore new targets or compounds. Mitochondria may serve as a potential therapeutic target for PTCL. A designed positively-charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV) and a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV (Pal-pHK-pKV) are bioactive amphiphilic peptide assemblies targeting the interaction between mitochondrial voltage dependent anion channel 1 (VDAC1) and hexokinase II (HKII).

METHODS

PTCL cell line H9 was treated with Pal-pHK-pKV and pHK-pKV, respectively. Cell proliferation in each group was measured by detecting cell viability and the corresponding marker Ki-67. Apoptosis was detected by immunofluorescence, flow cytometry and western blot. We also measured mitochondrial membrane potential, adenosine triphosphate (ATP) production, the cytochrome c distribution and the expression levels of B cell lymphoma 2 () and BCL-2 associated X protein (). Western blot was used to detect the activation of the extracellular regulated protein kinases (ERK) signaling pathway.

RESULTS

Pal-pHK-pKV and pHK-pKV with 20 µM blocked the interaction between VDAC1 and HKII, and detached HKII from mitochondria, which depolarized the mitochondrial membrane potential, induced mitochondria dysfunction, and decreased ATP production. The decreased ATP subsequently inhibited the activation of the ERK/BCL-2 pathway and increased the BAX/BCL-2 ratio. Cytochrome c was then released from the mitochondria and induced capase-3 activation and subsequently apoptosis. Additionally, decreased ATP induced the expression of and then apoptosis.

CONCLUSIONS

Mitochondria specific peptide amphiphiles induce mitochondrial dysfunction and provide a new approach for the treatment of PTCL.

摘要

背景

外周T细胞淋巴瘤（PTCL）是预后较差的侵袭性淋巴瘤，因此，迫切需要探索新的靶点或化合物。线粒体可能是PTCL的一个潜在治疗靶点。一个设计的带正电荷片段（pKV）锚定在特定的15个氨基酸序列（MIASHLLAYFFTELN）上，产生一种细胞穿透肽（pHK-pKV），并且一条脂链（Pal）与pHK-pKV的N端偶联（Pal-pHK-pKV），它们是靶向线粒体电压依赖性阴离子通道1（VDAC1）和己糖激酶II（HKII）之间相互作用的生物活性两亲性肽组装体。

方法

分别用Pal-pHK-pKV和pHK-pKV处理PTCL细胞系H9。通过检测细胞活力和相应标志物Ki-67来测量每组中的细胞增殖。通过免疫荧光、流式细胞术和蛋白质免疫印迹法检测细胞凋亡。我们还测量了线粒体膜电位、三磷酸腺苷（ATP）生成、细胞色素c分布以及B细胞淋巴瘤2（BCL-2）和BCL-2相关X蛋白（BAX）的表达水平。使用蛋白质免疫印迹法检测细胞外调节蛋白激酶（ERK）信号通路的激活。

结果

20μM的Pal-pHK-pKV和pHK-pKV阻断了VDAC1与HKII之间的相互作用，并使HKII从线粒体上脱离，这使线粒体膜电位去极化，诱导线粒体功能障碍，并降低ATP生成。ATP生成减少随后抑制了ERK/BCL-2通路的激活并增加了BAX/BCL-2比值。然后细胞色素c从线粒体释放，诱导半胱天冬酶-3激活并随后导致细胞凋亡。此外，ATP减少诱导了p53表达，然后导致细胞凋亡。