Abstract
Maintenance of energy (i.e. ATP) homeostasis is one of the most important tasks of a living cell. Tight control of this process allows cellular reactions to run at the lowest metabolic costs. Phosphotransfer reactions play an important role in this process and together form the cellular enzymatic network for high-energy phosphoryl transfer, required for safeguarding adequate cellular energy levels. The Adenylate kinase (AK)-catalyzed reaction is one of the 'evolutionary oldest' phosphotransfer reactions, mediated by several AK-isoforms in specific tissues at distinct subcellular localizations. The subject of this thesis, AK1, is found highly expressed in tissues with a high-energy turnover, such as skeletal muscle and heart, and also exists as a membrane-bound form (AK1Ø). Using an AK1 knockout mouse as a study model this thesis addresses the consequences of AK1 deletion and describes the functional role of AK1 in maintaining efficient energy flow in the skeletal and heart muscle. Metabolic rearrangements at the level of flux regulation, protein activity,and gene expression regulation, aimed at preservation of efficient energetic communication between ATP producing and utilizing sites, are accordingly described throughout the different chapters. We found that, by making the energy available stored in the pool of Ø-phosphoryls of ATP, the AK1-mediated metabolic circuit allows cellular energy metabolism to occur in a highly efficient mode, thereby increasing the tolerance to metabolic stress. Furthermore, by using molecular en electrophysiological approaches we demonstrate that AK1Ø is a functional adenylate kinase that might serve in communicating energetic or metabolic signals from cytosolic locales to spatially distinct compartments at or in the cell membrane
