Exploring the molecular interface between the HIF/hypoxia signalling pathway and mitochondria in cancer

探索癌症中 HIF/缺氧信号通路与线粒体之间的分子界面

• 批准号: MR/K002201/2
• 负责人: Margaret Ashcroft
• 金额: $ 27.69万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK002201%2F2
• 关键词: Exploring; molecular; interface; between; HIF

Most organisms need oxygen to survive and generate energy efficiently. Mitochondria are essential subcellular compartments, present within all animal cells that consume oxygen and generate chemical energy. When cellular oxygen levels change, an "oxygen-sensor" called HIF-1alpha increases and switches on specific genes in the nucleus. We have discovered a human gene (CHCHD4) that encodes two mitochondrial proteins that interact with HIF-1alpha. Furthermore, we have also found that HIF-1alpha protein localizes with mitochondria in cells. We have previously shown that CHCHD4 proteins are essential for regulating the amount of HIF-1alpha protein available in the cell when cells experience low oxygen levels (hypoxia). This is important, because high levels of HIF-1alpha are associated with several human diseases including heart and kidney disease, stroke and cancer, where hypoxia is a key contributing factor to the pathology and severity of the disease. The role of HIF-1alpha protein localization with mitochondria and binding to CHCHD4 protein is not known. Thus, the proposed work will explore the molecular interface between HIF-1alpha and mitochondria with specific focus on the role of the HIF-alpha:CHCHD4 interaction in regulating mitochondrial function and metabolism in tumour cells. This work will help us identify novel mechanisms for how tumour cells adapt to their hypoxia microenvironment.

大多数生物体需要氧气才能生存并有效地产生能量。线粒体是重要的亚细胞区室，存在于所有动物细胞中，消耗氧气并产生化学能。当细胞氧水平发生变化时，一种名为HIF-1 α的“氧传感器”就会增加，并启动细胞核中的特定基因。我们发现了一个人类基因（CHCHD 4），编码两种与HIF-1 α相互作用的线粒体蛋白。此外，我们还发现HIF-1 α蛋白在细胞内定位于线粒体。我们以前已经表明，CHCHD 4蛋白是必不可少的调节HIF-1 α蛋白的量在细胞中，当细胞经历低氧水平（缺氧）。这一点很重要，因为高水平的HIF-1 α与几种人类疾病有关，包括心脏病和肾病、中风和癌症，其中缺氧是导致疾病病理学和严重程度的关键因素。HIF-1 α蛋白定位于线粒体和与CHCHD 4蛋白结合的作用尚不清楚。因此，拟议的工作将探索HIF-1 α和线粒体之间的分子界面，特别关注HIF-1 α：CHCHD 4相互作用在调节肿瘤细胞线粒体功能和代谢中的作用。这项工作将帮助我们确定肿瘤细胞如何适应缺氧微环境的新机制。

项目成果

S79 Localised hypoxia enhances neutrophil extravasation and activation in interstitial lung disease

S79 间质性肺疾病中局部缺氧增强中性粒细胞外渗和活化

• DOI: 10.1136/thoraxjnl-2017-210983.85
• 发表时间: 2017
• 作者: Khawaja A

VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function.

• DOI: 10.3389/fonc.2018.00388
• 发表时间: 2018
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Briston T;Stephen JM;Thomas LW;Esposito C;Chung YL;Syafruddin SE;Turmaine M;Maddalena LA;Greef B;Szabadkai G;Maxwell PH;Vanharanta S;Ashcroft M
• 通讯作者: Ashcroft M

The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo.

线粒体氧化还原酶 CHCHD4 在体内以半氧化状态存在。

• DOI: 10.17863/cam.24511
• 发表时间: 2018
• 作者: Erdogan A

Mutations in mitochondrial DNA causing tubulointerstitial kidney disease.

• DOI: 10.1371/journal.pgen.1006620
• 发表时间: 2017-03
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Connor TM;Hoer S;Mallett A;Gale DP;Gomez-Duran A;Posse V;Antrobus R;Moreno P;Sciacovelli M;Frezza C;Duff J;Sheerin NS;Sayer JA;Ashcroft M;Wiesener MS;Hudson G;Gustafsson CM;Chinnery PF;Maxwell PH
• 通讯作者: Maxwell PH

Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria.

探索缺氧诱导因子信号传导与线粒体之间的分子界面。

• DOI: 10.17863/cam.36733
• 发表时间: 2019
• 作者: Thomas L