Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate
Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate
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DOI：
10.1158/0008-5472.can-20-2936
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发表时间：
2021-07-01
期刊：
影响因子：
11.2
通讯作者：
Favier, Judith
中科院分区：
文献类型：
--
作者：
Goncalves, Judith;Moog, Sophie;Favier, Judith
琥珀酸脱氢酶是三羧酸循环和电子传递链中的关键酶。琥珀酸脱氢酶的所有四个亚基都是易患副神经节瘤的肿瘤抑制基因，但只有 SDHB 亚基的突变与转移风险增加相关。在这里，我们生成了 Sdhd 敲除嗜铬细胞系，并将其与 Sdhb 缺陷细胞进行比较。两种细胞类型均表现出相似的 SDH 功能丧失、代谢适应和琥珀酸积累。相比之下，与Sdhd(-/-)细胞相比，Sdhb(-/-)细胞表现出与DNA高甲基化增加相关的间质转化标志和更强的假性缺氧表型。在缺乏 NRF2 激活的情况下，SDHB 的缺失会导致氧化应激增加，而氧化应激与铁和铜稳态失调相关。高剂量抗坏血酸加剧了线粒体活性氧的增加，导致Sdhb(-/-)细胞死亡。这些数据建立了一种将氧化应激与铁稳态联系起来的机制，这种机制特别发生在 Sdhb 缺陷细胞中，并可能促进转移。他们还强调高剂量抗坏血酸是治疗 SDHB 相关癌症的一种有前途的治疗策略。 意义 不同琥珀酸脱氢酶亚基的丧失可能导致不同的细胞和肿瘤表型，与 SDHB 突变后更强的 2-OG 依赖性双加氧酶抑制、铁超载和 ROS 积累相关。
Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cyde and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, hut only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an Sdhd knockout chromaffin cell line and compared it with Sdhb-deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, Sdhb(-/-) cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with Sdhd(-/-) cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in Sdhb(-/-) cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in Sdhb-deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers.Significance Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation.