A mathematical model of calcium dynamics: Obesity and mitochondria-associated ER membranes

Multiple cellular organelles tightly orchestrate intracellular calcium (Ca(2+)) dynamics to regulate cellular activities and maintain homeostasis. The interplay between the endoplasmic reticulum (ER), a major store of intracellular Ca(2+), and mitochondria, an important source of adenosine triphosphate (ATP), has been the subject of much research, as their dysfunction has been linked with metabolic diseases. Interestingly, throughout the cell’s cytosolic domain, these two organelles share common microdomains called mitochondria-associated ER membranes (MAMs), where their membranes are in close apposition. The role of MAMs is critical for intracellular Ca(2+) dynamics as they provide hubs for direct Ca(2+) exchange between the organelles. A recent experimental study reported correlation between obesity and MAM formation in mouse liver cells, and obesity-related cellular changes that are closely associated with the regulation of Ca(2+) dynamics. We constructed a mathematical model to study the effects of MAM Ca(2+) dynamics on global Ca(2+) activities. Through a series of model simulations, we investigated cellular mechanisms underlying the altered Ca(2+) dynamics in the cells under obesity. We predict that, as the dosage of stimulus gradually increases, liver cells from obese mice will reach the state of saturated cytosolic Ca(2+) concentration at a lower stimulus concentration, compared to cells from healthy mice.