Role of cardiac ion pumps, channels, and exchangers on regulation of mitochondrial bioenergetics

Membrane ion pumps and channels are essential key players in intracellular function and communication with other cells, e.g., nutrient uptake and bioelectrical communication. The cation exchangers Na + , H + , Ca 2+ and K + do more than simply rebalance ions and maintain ion homeostasis; they play crucial roles in modulating overall cellular bioenergetics. This review aims to describe how these cation gradients are formed and maintained by examining the ion flux mediated by each pump, channel, and exchanger and by integrating their functions across the cell and mitochondrial membranes. Most of this information is derived from the large amount of work in cardiac muscle cells where fluctuations in ion fluxes occur second by second. First is presented a review of the sarcolemmal and sarco(endo)plasmic reticular ion pumps, channels, and exchangers because mitochondrial ion fluxes are affected by the cytosolic ion concentrations. Then mitochondrial ion fluxes regulated by the mitochondrial ion pumps, channels, and exchangers are discussed. There are prior excellent reviews on mitochondrial cation fluxes, so the goal is to update the narrative with more recent publications that expand our understanding, with some controversies, of cell and mitochondrial cation fluxes on regulating a multitude of cell and organelle functions. Updates are furnished on the putative identity and function of the four major mitochondrial cation exchangers. Also, an emphasis is placed on updating the role of transmembrane ion fluxes on impacting mitochondrial bioenergetics by altering the proton motive force and oxidative phosphorylation. A few important historical reports are included with the recent studies.