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

• Published in: PLoS computational biology Vol. 15; no. 8; p. e1006661
• Main Authors: Han, Jung Min, Periwal, Vipul
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2019; Public Library of Science (PLoS)
• Subjects: Adenosine triphosphate; Adenosine Triphosphate - metabolism; Analysis; Animals; Apposition; ATP; Biology and Life Sciences; Calcium; Calcium (intracellular); Calcium (Nutrient); Calcium ions; Calcium Signaling - physiology; Calcium signalling; Chemical kinetics; Computational Biology; Computer Simulation; Correlation analysis; Diabetes; Dynamics; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Hepatocytes; Hepatocytes - metabolism; Homeostasis; Humans; Inositol Phosphates - metabolism; Insulin resistance; Intracellular; Investigations; Kidney diseases; Laboratories; Liver; Mathematical analysis; Mathematical Concepts; Mathematical models; Medicine and Health Sciences; Membranes; Metabolic disorders; Metabolic Networks and Pathways; Mice; Mitochondria; Mitochondria - metabolism; Mitochondria, Liver - metabolism; Mitochondrial membrane; Models, Biological; Obesity; Obesity - metabolism; Organelles; Research and Analysis Methods; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; United States; United States > US; Maryland
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1006661

Multiple cellular organelles tightly orchestrate intracellular calcium (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 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 Ca2+ dynamics as they provide hubs for direct Ca2+ 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 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 predict 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.