Integration of Adenylate Kinase and Glycolytic and Glycogenolytic Circuits in Cellular Energetics

Emerging evidence indicates that adenylate kinase and glycolytic/glycogenolytic phosphotransfer enzyme circuits are essential parts of cardiac system bioenergetics, playing a significant role in muscle energetics by delivering high-energy phosphoryls and conveying energy demand signals to ATP-generating pathways and metabolic sensors. Adenylate kinase phosphotransfer promptly respondsto metabolic imbalances, facilitating transfer and utilization of both g-and bphosphoryls of the ATP molecule and maintaining energy economy. Adenylate kinase-mediated intracellular AMP signaling coupled with AMP-responsive elements such as AMP-sensitive protein kinase (AMPK), ATP-sensitive potassium channels (KATP), and AMP-sensitive metabolic enzymes, along with adenosine signaling, comprise a key metabolic sensing system regulating vital cellular processes. Localized in close proximity to metabolic sensors, adenylate kinase-catalyzed AMP signal generation and nucleotide exchange regulate the dynamics and frequency of ligand switching in the intimate sensing zone, facilitating the decoding of cellular information. By instigating AMP signaling, adenylate kinase regulates the activity of glycolytic and glycogenolytic enzymes and provides an integrative node for bioenergetic pathways to respond with high fidelity to increased energy demand. Genetic deficiency of the cytosolic AK1 isoform results in defective muscle energetics and AMP signaling, compromising the response to metabolic stress. Spatial extension of the glycolytic pathway indicates that it comprises a network of phosphotransfer circuits and metabolite shuttles, which facilitate high-energy phosphoryl delivery and lactate/pyruvate and Pi shuttling and thus maintain cellular energy and redox balance. The dynamics of glycogen utilization and synthesis, processes that occur close to myofibrillar and mitochondrial compartments, also suggest the existence of a glycogenolytic energetic circuit. In the proposed glycogen energetic network model, mitochondrial metabolic energy, invested into glycogen through locally generated UTP and G-6-P/G-1-P, is released during glycogenolysis at ATP utilization sites in myofibrils and other cellular compartments. Thus, systemic integration of different energetic and metabolic signaling pathways ensures cellular energy homeostasis and an adequate response to a broad range of functional activities and stress challenges.