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

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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.