Mitochondrial Modulation of Intracellular Ca2+Signaling

Abstract

IP3-mediated Ca2+release plays a fundamental role in many cell signaling processes and has been the subject of numerous modeling studies. Only recently has the important role that mitochondria play in the dynamics of intracellular Ca2+signaling begun to be considered in experimental work and in computational models. Mitochondria sequester large amounts of Ca2+and thus have a modulatory effect on intracellular Ca2+signaling, and mitochondrial uptake of Ca2+, in turn, has a regulatory effect on mitochondrial function. Here we integrate a well-established model of IP3-mediated Ca2+signaling with a detailed model of mitochondrial Ca2+handling and metabolic function. The incorporation of mitochondria results in oscillations in a bistable formulation of the IP3 model, and increasing metabolic substrate decreases the frequency of these oscillations consistent with the literature. Ca2+spikes from the cytosol are communicated into mitochondria and are shown to induce realistic metabolic changes. The model has been formulated using a modular approach that is easy to modify and should serve as a useful basis for the investigation of questions regarding the interaction of these two systems.