Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

Intracellular molecules are transported by motor proteins or move by diffusion resulting from random molecular motion. Cardiomyocytes are packed with structures that are crucial for function, but also confine the diffusional spaces, providing cells with a means to control diffusion. They form compartments in which local concentrations are different from the overall, average concentrations. For example, calcium and cyclic AMP are highly compartmentalized, allowing these versatile second messengers to send different signals depending on their location. In energetic compartmentalization, the ratios of AMP and ADP to ATP are different from the average ratios. This is important for the performance of ATPases fuelling cardiac excitation‐contraction coupling and mechanical work. A recent study suggested that compartmentalization modulates the activity of creatine kinase and adenylate kinase in situ. This could have implications for energetic signaling through, for example, AMP‐activated kinase. It highlights the importance of taking compartmentalization into account in our interpretation of cellular physiology and developing methods to assess local concentrations of AMP and ADP to enhance our understanding of compartmentalization in different cell types. Cardiomyocytes are packed with structures that are critical for their function and lead to the compartmentalization of the cells. This is crucial for cardiac function and signaling. In this Review, we discuss how compartmentalization affects protein localization, signaling, and energy transfer. In particular, we explain the hierarchical organization of energetic compartments and discuss how they impact function and energetic signaling.