Model of mitochondrial function

Periwal, Vipul

Abstract

Multiple cellular organelles tightly orchestrate intracellular Ca2+ dynamics to regulate cellular activities and maintain homeostasis. The interplay between the endoplasmic reticulum (ER), a major store of intracellular Ca2+, and mitochondria, an important source of adenosine triphos- phate (ATP), has been the subject of much research. Interestingly, throughout the cells cytosolic domain, these two organelles share common microdomains called mitochondria-associated ER mem- branes (MAMs), where their membranes are in close apposition. The role of MAMs is critical for intracellular Ca2+ dynamics as they provide essential hubs for direct Ca2+ exchange between the organelles. A recent experimental study reported that liver cells from obese mice have different cellular properties from those of healthy animals, in particular, the degree of MAM formation, the expression levels of Ca2+ releasing channels on the ER membrane and that of Ca2+ sequestering channels on mitochondrial membrane, and observed that they exhibit different Ca2+ dynamics. We constructed a mathematical model to study the effects of MAM Ca2+ dynamics on global Ca2+ activities. Through a series of model simulations, we investigated cellular mechanisms underlying the altered Ca2+ dynamics in the cells under obesity. We found that the formation of MAMs is negatively correlated with the amplitude of cytosolic Ca2+ activities, but positively correlated with that of mitochondrial Ca2+ dynamics and the overall frequency of Ca2+ oscillations. The over-expression of ER Ca2+ releasing channels increased Ca2+ amplitudes in both organelles, as well as the oscillation frequency. Lastly, up-regulating mitochondrial Ca2+ channels increased the magnitude of mitochondrial Ca2+ activities, while decreasing that of cytosolic Ca2+ activities. In- terestingly, the oscillation frequency was decreased. We suggest that, as the dosage of stimulus gradually increases, liver cells from obese mice will reach the state of saturated cytosolic Ca2+ concentration at a lower stimulus concentration, compared to cells from healthy mice.