The low conductance mitochondrial permeability transition pore confers excitability and CICR wave propagation in a computational model

Mitochondria have long been known to sequester cytosolic Ca2+ and even to shape intracellular patterns of endoplasmic reticulum-based Ca2+ signaling. Evidence suggests that the mitochondrial network is an excitable medium which can demonstrate independent Ca2+ induced Ca2+ release via the mitochondrial permeability transition. The role of this excitability remains unclear, but mitochondrial Ca2+ handling appears to be a crucial element in diverse diseases as diabetes, neurodegeneration and cardiac dysfunction that also have bioenergetic components. In this paper, we extend the modular Magnus–Keizer computational model for respiration-driven Ca2+ handling to include a permeability transition based on a channel-like pore mechanism. We demonstrate both excitability and Ca2+ wave propagation accompanied by depolarizations qualitatively similar to those reported in cell and isolated mitochondria preparations. These waves depend on the energy state of the mitochondria, as well as other elements of mitochondrial physiology. Our results support the concept that mitochondria can transmit state dependent signals about their function across the mitochondrial network. Our model provides the tools for predictions about the internal physiology that leads to this qualitatively different Ca2+ excitability seen in mitochondria.