Redox regulation of human adenylate kinase 2 (AK2), an essential key controller of energy metabolism

人腺苷酸激酶 2 (AK2) 的氧化还原调节，能量代谢的关键控制器

• 批准号: 251546152
• 负责人: Professor Dr. Jan Riemer
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/251546152?language=en
• 关键词: Redox; regulation; human; adenylate; kinase

The mitochondrial intermembrane space (IMS) takes a critical role in mitochondrial physiology. IMS proteins are involved in important metabolic processes, protein import and folding, signaling events and the initiation of apoptosis. By characterising the substrate spectrum of import pathways into the IMS, we identified adenylate kinase 2 (AK2) as target of the IMS disulphide formation machinery. AK2 is an essential protein that controls energy metabolism and AMPK-dependent signaling. Patients lacking this enzyme suffer from a fatal immunodeficiency due to an arrest in the differentiation of certain immune cells. Interestingly, nothing is known about the mechanisms of mitochondrial AK2 import and its regulation as well as the regulation of its activity once it has matured in the IMS. Our preliminary data suggest that AK2 is the target of the IMS import receptor and oxidoreductase CHCHD4/Mia40. Moreover, redox-dependent AK2 import appears to be controlled by a cytosolic quality control machinery that minimizes cytosolic mislocalisation of AK2. Lastly, AK2 also appears to be subject to thiol-disulfide-dependent redox regulation in the IMS. The aim of this project is to understand in molecular detail these two processes and obtain insights into the physiological consequences of a failure of these processes. Our findings will thereby help to better understand cellular energy metabolism as well as the signaling network that controls it.

线粒体膜间隙（IMS）在线粒体生理学中起着关键作用。IMS蛋白参与重要的代谢过程、蛋白质输入和折叠、信号事件和细胞凋亡的启动。通过表征IMS的输入途径的底物谱，我们确定腺苷酸激酶2（AK 2）作为IMS二硫化物形成机制的靶点。AK 2是控制能量代谢和AMPK依赖性信号传导的必需蛋白。缺乏这种酶的患者由于某些免疫细胞的分化停滞而遭受致命的免疫缺陷。有趣的是，对于线粒体AK 2输入的机制及其调节以及一旦其在IMS中成熟后对其活性的调节一无所知。我们的初步数据表明，AK 2是IMS输入受体和氧化还原酶CHCHD 4/Mia 40的靶标。此外，氧化还原依赖性AK 2输入似乎是由胞质质量控制机制控制的，该机制使AK 2的胞质错误定位最小化。最后，AK 2似乎也受到硫醇-二硫化物依赖性氧化还原调节的IMS。该项目的目的是在分子上详细了解这两个过程，并深入了解这些过程失败的生理后果。因此，我们的发现将有助于更好地了解细胞能量代谢以及控制它的信号网络。