Parthanatos is a type of programmed cell death initiated by over-activated poly (ADP-ribose) polymerase 1 (PARP1). Nuclear translocation of apoptosis inducing factor (AIF) is a prominent feature of parthanatos. But it remains unclear how activated nuclear PARP1 induces mitochondrial AIF translocation into nuclei. Evidence has shown that deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells via induction of excessive ROS. In this study we explored the downstream signal of activated PARP1 to induce nuclear translocation of AIF in DPT-triggered glioma cell parthanatos. We showed that treatment with DPT (450 nM) induced PARP1 over-activation and Tax1 binding protein 1 (TAX1BP1) distribution to mitochondria in human U87, U251 and U118 glioma cells. PARP1 activation promoted TAX1BP1 distribution to mitochondria by depleting nicotinamide adenine dinucleotide (NAD⁺). Knockdown of TAX1BP1 with siRNA not only inhibited TAX1BP1 accumulation in mitochondria, but also alleviated nuclear translocation of AIF and glioma cell death. We demonstrated that TAX1BP1 enhanced the activity of respiratory chain complex I not only by upregulating the expression of ND1, ND2, NDUFS2 and NDUFS4, but also promoting their assemblies into complex I. The activated respiratory complex I generated more superoxide to cause mitochondrial depolarization and nuclear translocation of AIF, while the increased mitochondrial superoxide reversely reinforced PARP1 activation by inducing ROS-dependent DNA double strand breaks. In mice bearing human U87 tumor xenograft, administration of DPT (10 mg· kg⁻¹ ·d⁻¹, i.p., for 8 days) markedly inhibited the tumor growth accompanied by NAD⁺ depletion, TAX1BP1 distribution to mitochondria, AIF distribution to nuclei as well as DNA DSBs and PARP1 activation in tumor tissues. Taken together, these data suggest that TAX1BP1 acts as a downstream signal of activated PARP1 to trigger nuclear translocation of AIF by activation of mitochondrial respiratory chain complex I.

Parthanatos 是一种由过度激活的聚（ADP-核糖）聚合酶 1 (PARP1) 引发的程序性细胞死亡。凋亡诱导因子（AIF）的核易位是parthanatos的一个显着特征。但目前尚不清楚激活的核 PARP1 如何诱导线粒体 AIF 易位到细胞核中。有证据表明，脱氧鬼臼毒素 (DPT) 通过诱导过量的 ROS 来诱导神经胶质瘤细胞的死亡。在这项研究中，我们探索了激活的 PARP1 的下游信号，以诱导 DPT 触发的神经胶质瘤细胞 parthanatos 中 AIF 的核转位。我们发现，在人 U87、U251 和 U118 神经胶质瘤细胞中，DPT (450 nM) 处理可诱导 PARP1 过度激活，并使 Tax1 结合蛋白 1 (TAX1BP1) 分布至线粒体。^{PARP1 激活通过消耗烟酰胺腺嘌呤二核苷酸 (NAD +} )促进 TAX1BP1 分布到线粒体。用 siRNA 敲低 TAX1BP1 不仅抑制了 TAX1BP1 在线粒体中的积累，而且还减轻了 AIF 的核转位和神经胶质瘤细胞死亡。我们证明TAX1BP1不仅通过上调ND1、ND2、NDUFS2和NDUFS4的表达来增强呼吸链复合物I的活性，而且还促进它们组装成复合物I。激活的呼吸链复合物I产生更多的超氧化物，导致线粒体去极化和核AIF 的易位，而线粒体超氧化物的增加则通过诱导 ROS 依赖性 DNA 双链断裂，反向增强了 PARP1 的激活。在携带人 U87 肿瘤异种移植物的小鼠中，施用 DPT（10 mg·kg ^-1  ·d ^-1，腹膜内，持续 8 天）显着抑制肿瘤生长，并伴随着 NAD ⁺消耗，TAX1BP1 分布到线粒体，AIF 分布到细胞核，如下所示以及肿瘤组织中 DNA DSB 和 PARP1 的激活。总而言之，这些数据表明 TAX1BP1 作为激活的 PARP1 的下游信号，通过激活线粒体呼吸链复合物 I 来触发 AIF 的核转位。