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

线粒体膜间隙（IMS）在线粒体生理中起着至关重要的作用。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。通过表征进入IMS的底物谱，我们确定了腺苷酸激酶2 （AK2）是IMS二硫化物形成机制的靶标。AK2是控制能量代谢和ampk依赖性信号的重要蛋白。缺乏这种酶的患者由于某些免疫细胞分化受阻而遭受致命的免疫缺陷。有趣的是，对于线粒体AK2的输入及其调控机制，以及在IMS中成熟后对其活性的调控，我们一无所知。我们的初步数据表明AK2是IMS输入受体和氧化还原酶CHCHD4/Mia40的靶点。此外，氧化还原依赖性AK2的输入似乎受到细胞质质量控制机制的控制，该机制可以最大限度地减少AK2的细胞质错定位。最后，AK2在IMS中似乎也受二硫醇依赖的氧化还原调节。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理解细胞能量代谢以及控制它的信号网络。

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.