Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors
Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors
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DOI：
10.4161/cbt.4.12.2233
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发表时间：
2005-12-01
影响因子：
3.6
通讯作者：
Singh, KK
中科院分区：
文献类型：
--
作者：
Desouki, MM;Kulawiec, M;Singh, KK
在细胞生长、细胞死亡、有丝分裂、血管生成和肿瘤发生等过程中，ROS是细胞内信号转导的开关。ROS是线粒体氧化磷酸化(OXPHOS)的副产物。据估计，在OXPHOS过程中，2-4%的氧气消耗被转化为ROS。除线粒体外，NADPH-氧化酶1(Nox1)还在细胞内产生大量的ROS。在这篇文章中，我们验证了线粒体控制Nox1氧化还原信号的假设，以及对该信号的失去控制有助于肿瘤的发生。我们分析了Nox1在线粒体基因敲除(Rho(0))细胞系和通过将野生型线粒体转移到Rho(0)细胞中线粒体基因恢复的等基因胞质细胞系中的表达。我们的研究首次揭示了线粒体基因的失活导致Nox1的下调，而野生型线粒体基因的转移使Nox1的表达恢复到与亲本细胞系相当的水平。与Nox1的下调一致，我们发现Rho(0)细胞含有低水平的超氧阴离子，当野生型线粒体转移恢复Nox1的表达时，胞质细胞中的超氧阴离子水平反转到亲代水平。线粒体超氧化物歧化水平的增加也增加了亲本细胞中Nox1的表达。共聚焦显微镜研究表明，Nox1定位于线粒体。Nox1在乳腺肿瘤(86%)和卵巢肿瘤(71%)中高表达，其表达与线粒体DNA编码的细胞色素C氧化酶表达呈正相关。本文描述的我们的研究证明了线粒体和NADPH氧化酶之间存在串扰。此外，我们的研究表明，线粒体控制着Nox1氧化还原信号，该信号的失控有助于乳腺癌和卵巢肿瘤的发生。
Reactive oxygen species (ROS) function as cellular switches for signaling cascade involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox1 redox signaling and the loss of control of this signaling contribute to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (rho(0)) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into rho(0) cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that rho(0) cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.