It has been shown that calcium regulation is aberrant in organelles in the context of metabolic diseases, particularly in the liver and adipose tissue. Our work specifically displays how these disruptions in calcium homeostasis can lead to hallmarks of obesity and diabetes: increased ER stress, increased glucose production, and abrogated insulin sensitivity. This has led to our investigations of several critical mechanisms that lead to this calcium dysregulation, namely through ER and mitochondria calcium regulatory proteins such as STIM, IP3R1, and MCU.
Calcium, the most abundant ion in the body, is a ubiquitous and robust signaling molecule necessary for muscle contraction, hormone secretion, organelle communication, cell motility, fertilization, and cell growth. The tight regulation of cellular Ca2+ concentration is crucial for these functions, and alterations in its signaling networks upon metabolic stress are implicated in the mechanisms of many pathologies.
Organelles interact at contact sites, and of particular interest to our group are ER-mitochondria contact sites, or mitochondria associated membranes (MAMs). These dynamically regulated interactions between the ER and the mitochondrial membranes are increased in obesity, consequently increasing calcium efflux from the ER through IP3R channels and influx into the mitochondria through mitochondrial calcium uniporter (MCU). Changes in the profile of these contact sites can lead to the detrimental effects of mitochondrial calcium overload, oxidative stress, and pJNK stress signaling. More recently we have identified a key mechanism whereby ER calcium regulation at plasma membrane-ER contact sites by an ER calcium sensing protein, STIM, is defective in obese hepatocytes. We hope to learn more about the metabolic effects of this versatile signaling molecule, and examine potential alterations in other tissues that are important for our body's metabolic mission. We hope to utilize this knowledge to create potential novel therapeutics that involve proper regulation of calcium in metabolic diseases.
Arruda AP, Pers BM, Parlakgul G, Güney E, Goh T, Cagampan E, Lee GY, Goncalves RL, Hotamışlıgil GS. Defective STIM-mediated store operated calcium entry in hepatocytes leads to metabolic dysfunction in obesity. eLife. 2017 Dec; DOI:10.7554/eLife.29968. Full Text
Fu S, Yang L, Li P, Hoffman O, Dicker L, Hide W, Lin X, Watkins, SM, Ivanov A, Hotamışlıgil GS. Aberrant lipid metabolism disrupts calcium homeostasis causing liver ER stress in obesity. Nature, 2011, 473; 528-531. Abstract | PDF