Mitochondrial STAT3 regulates antioxidant gene expression through complex I-derived NAD in triple negative breast cancer.
Mitochondrial STAT3 regulates antioxidant gene expression through complex I-derived NAD in triple negative breast cancer.
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DOI：
10.1002/1878-0261.12928
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发表时间：
2021-05
影响因子：
6.6
通讯作者：
Levy DE
中科院分区：
文献类型：
--
作者：
Lahiri T;Brambilla L;Andrade J;Askenazi M;Ueberheide B;Levy DE
信号转导和转录激活因子3(STAT3)是一种转录因子，在炎症和肿瘤发生中起重要作用。一小部分STAT3定位于线粒体，在那里它通过调节线粒体功能来增强肿瘤的发生，包括调节呼吸和氧化还原状态。我们展示了线粒体STAT3调节三阴性乳腺癌细胞氧化还原动态平衡的新机制。STAT3的缺失降低了复合体I脱氢酶的活性，损害了NAD+的再生，导致谷胱甘肽生物合成基因和其他抗氧化剂基因的表达受损。表达线粒体限制性的STAT3或补充细胞NAD池可以恢复抗氧化基因的表达，通过表达不依赖于STAT3的酵母脱氢酶NDI1来补充NADH脱氢酶的活性也是如此。这些NAD调控的过程通过促进克隆细胞的生长和迁移而促进了恶性表型的形成。邻近相互作用和蛋白质下拉分析确定了与线粒体STAT3相关的复合体I的三个组分，为线粒体STAT3如何影响复合体I的活性提供了潜在的机制基础。我们的数据证明了一种新的机制，线粒体STAT3通过受复合体I脱氢酶活性调节的逆行NAD+信号间接控制抗氧化基因的调节。STAT3与线粒体中的呼吸复合体I相互作用，导致NADH脱氢酶活性增强，促进呼吸过程中NAD+的有效再生。NAD+作为一种逆行信号，将线粒体代谢与核基因表达的变化联系起来，导致抗氧化基因的诱导，有助于维持氧化还原平衡，促进恶性细胞的生长、存活和迁移。
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor with roles in inflammation and tumorigenicity. A fraction of STAT3 localizes in mitochondria, where it augments tumorigenesis via regulation of mitochondrial functions, including modulation of respiration and redox status. We show a novel mechanism for mitochondrial STAT3 regulation of redox homeostasis in triple‐negative breast cancer cells. Loss of STAT3 diminished complex I dehydrogenase activity and impaired NAD+ regeneration, leading to impaired expression of glutathione biosynthetic genes and other antioxidant genes. Expressing mitochondrially restricted STAT3 or replenishment of the cellular NAD pool restored antioxidant gene expression, as did complementation of the NADH dehydrogenase activity by expression of the STAT3‐independent yeast dehydrogenase, NDI1. These NAD‐regulated processes contributed to malignant phenotypes by promoting clonal cell growth and migration. Proximity interaction and protein pull‐down assays identified three components of complex I that associated with mitochondrial STAT3, providing a potential mechanistic basis for how mitochondrial STAT3 affects complex I activity. Our data document a novel mechanism through which mitochondrial STAT3 indirectly controls antioxidant gene regulation through a retrograde NAD+ signal that is modulated by complex I dehydrogenase activity. STAT3 interacts with respiratory complex I in mitochondria, leading to enhanced NADH dehydrogenase activity, facilitating efficient regeneration of NAD+ during respiration. NAD+ acts as a retrograde signal linking mitochondrial metabolism to changes in nuclear gene expression, leading to induction of antioxidant genes that contribute to the maintenance of redox balance and malignant cell growth, survival, and migration.
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影响因子：
3.7
作者：
Gough DJ;Koetz L;Levy DE
通讯作者：
Levy DE
影响因子：
4.4
作者：
Indo, Hiroko P.;Davidson, Mercy;Majima, Hideyuki J.
通讯作者：
Majima, Hideyuki J.
影响因子：
4.8
作者：
Amat, Ramon;Planavila, Anna;Villarroya, Francesc
通讯作者：
Villarroya, Francesc
DOI：
10.15252/embj.201592629
发表时间：
2016-03-15
期刊：
The EMBO journal
影响因子：
--
作者：
Carbognin E;Betto RM;Soriano ME;Smith AG;Martello G
通讯作者：
Martello G
肿瘤中的血红素加氧酶-1：它是一个假朋友吗？
影响因子：
6.6
作者：
Jozkowicz A;Was H;Dulak J
通讯作者：
Dulak J