Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection.
Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection.
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DOI：
10.3389/fcimb.2022.1026293
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发表时间：
2022
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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T细胞对控制病毒感染至关重要；然而，在病毒感染期间抑制其反应的机制仍然不完全清楚。在这里，我们研究了线粒体拓扑异构酶1(Top1mt)抑制在线粒体功能障碍和T细胞调节异常中的作用和机制，并将其与经Top1抑制剂喜树碱(CPT)治疗后的健康人CD4T细胞进行了比较。我们发现，在丙型肝炎病毒感染者和HIV感染者的CD4T细胞线粒体中，Top1mt蛋白水平和酶活性显著降低，并形成Top1裂解复合体(Top1cc)。值得注意的是，CPT处理健康的CD4T细胞会引起类似的变化，包括抑制Top1mt，在线粒体中积累Top1cc，增加PARP1裂解，减少mtDNA拷贝数。这些分子变化通过多条信号通路导致线粒体功能障碍、T细胞失调和细胞程序性死亡，概括了我们在丙型肝炎病毒和艾滋病病毒感染患者的CD4T细胞中检测到的表型。此外，用CPT治疗来自丙型肝炎病毒或艾滋病毒患者的CD4T细胞进一步增加了细胞和线粒体反应性氧物种(ROS)的产生和细胞凋亡，显示了Top1在防止线粒体DNA损伤和细胞死亡方面的关键作用。这些结果为病毒感染过程中免疫失调的分子机制提供了新的见解，并表明在慢性丙型肝炎或艾滋病病毒感染过程中抑制Top1可以导致线粒体DNA损伤和T细胞功能障碍。因此，重组Top1mt蛋白可以恢复慢性病毒感染者线粒体DNA的拓扑结构和T细胞功能。
T cells are crucial for controlling viral infections; however, the mechanisms that dampen their responses during viral infections remain incompletely understood. Here, we studied the role and mechanisms of mitochondrial topoisomerase 1 (Top1mt) inhibition in mitochondrial dysfunction and T cell dysregulation using CD4 T cells from patients infected with HCV or HIV and compared it with CD4 T cells from healthy individuals following treatment with Top1 inhibitor - camptothecin (CPT). We found that Top1mt protein levels and enzymatic activity are significantly decreased, along with Top1 cleavage complex (Top1cc) formation, in mitochondria of CD4 T cells from HCV- and HIV-infected patients. Notably, treatment of healthy CD4 T cells with CPT caused similar changes, including inhibition of Top1mt, accumulation of Top1cc in mitochondria, increase in PARP1 cleavage, and decrease in mtDNA copy numbers. These molecular changes resulted in mitochondrial dysfunction, T cell dysregulation, and programmed cell death through multiple signaling pathways, recapitulating the phenotype we detected in CD4 T cells from HCV- and HIV-infected patients. Moreover, treatment of CD4 T cells from HCV or HIV patients with CPT further increased cellular and mitochondrial reactive oxygen species (ROS) production and cell apoptosis, demonstrating a critical role for Top1 in preventing mtDNA damage and cell death. These results provide new insights into the molecular mechanisms underlying immune dysregulation during viral infection and indicate that Top1 inhibition during chronic HCV or HIV infection can induce mtDNA damage and T cell dysfunction. Thus, reconstituting Top1mt protein may restore the mtDNA topology and T cell functions in humans with chronic viral infection.
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影响因子：
4.8
作者：
Boulares, AH;Yakovlev, AG;Smulson, M
通讯作者：
Smulson, M
影响因子：
4.8
作者：
Boettinger, Lena;Oeljeklaus, Silke;Becker, Thomas
通讯作者：
Becker, Thomas
DOI：
10.1073/pnas.1215006109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Ahn, Jeonghyun;Gutman, Delia;Barber, Glen N.
通讯作者：
Barber, Glen N.
影响因子：
7.3
作者：
Cao D;Khanal S;Wang L;Li Z;Zhao J;Nguyen LN;Nguyen LNT;Dang X;Schank M;Thakuri BKC;Zhang J;Lu Z;Wu XY;Morrison ZD;El Gazzar M;Ning S;Moorman JP;Yao ZQ
通讯作者：
Yao ZQ
影响因子：
64.8
作者：
通讯作者：
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