Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy
Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy
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DOI：
10.1073/pnas.1404171111
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发表时间：
2014-09-30
影响因子：
11.1
通讯作者：
Kung, Hsing-Jien
中科院分区：
文献类型：
--
作者：
Changou, Chun A.;Chen, Yun-Ru;Kung, Hsing-Jien
自噬是营养饥饿过程中主要的分解代谢促生存途径。然而，过度的自噬可能具有细胞毒性，导致细胞死亡，但其机制仍然难以捉摸。精氨酸饥饿已经成为几种类型癌症的潜在疗法，这是由于它们的精氨酸代谢的肿瘤选择性缺陷。我们在这里证明，精氨酸脱亚氨酶精氨酸消耗诱导的细胞毒性自噬在乙酰氨基琥珀酸合成酶（ASS 1）缺陷的前列腺癌细胞。先进的显微镜下分析剥夺了甘氨酸的垂死细胞揭示了一种新的表型与巨大的自噬体形成，核膜破裂，和组蛋白相关的DNA泄漏的自噬体，我们将称为染色质自噬，或chromophagy。此外，核内膜（lamin A/C）发生局部重排，外膜（NUP 98）与自噬体膜部分融合。进一步的分析表明，长期精氨酸耗竭损害线粒体氧化磷酸化功能和去极化线粒体膜电位。因此，活性氧（ROS）的生产显着增加，在细胞溶质和线粒体组分，可能导致DNA损伤积累。添加ROS清除剂N-乙酰半胱氨酸或敲低ATG 5或BECLIN 1减弱了噬色表型。我们的数据揭示了一种非典型的自噬相关的死亡途径，并表明线粒体损伤是连接精氨酸饥饿和噬色素在两个不同的细胞区室的核心。
Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.