Altered Mitochondria Associated Membranes & Inflammation: Novel Insights Into Immuno-Metabolism

Abstract Type 2 diabetes (T2D) is a metabolic disorder affecting 463 million people in the Unites States1.T2D is characterized primarily by hyperglycemia and inflammation driven insulin resistance2. Hyperglycemia leads to generation of reactive oxygen species (ROS) and oxidative stress in the mitochondria3. ROS also causes endoplasmic reticulum (ER) stress4. There is a tight interconnection between the ER and mitochondria stress through mitochondrial-associated membranes (MAMs) that fuel a vicious cycle of stress-mediated organelle dysfunction. MAMs orchestrate the protein folding and calcium buffering that in turn affect organelle homeostasis and cellular signaling pathways to control cell and organismal metabolism5,6. These findings imply a role of altered MAM and inflammatory mechanisms underlying insulin resistance in the development of diabetes, yet a large gap exists in how inflammation influences the structure, signaling, and functions of MAMs in diabetes remains elusive. Therefore, we hypothesize that inflammation induced changes in MAMs further promote inflammatory profiles and additionally impair calcium shuttling between ER and mitochondria in PBMCs. We propose the following specific aims to investigate mechanisms underlying chronic inflammation exacerbated diabetes by investigating changes in the MAMs in the immune cells from T2D subjects. Defining mechanisms driving T cell inflammation will significantly enhance our current appreciation of inflammation towards the goal of improving life span. The long-term goal of this project is to identify specific mechanisms that regulate the MAM structure and function, that cans serve as drug target for prevention and/or treatment strategies in T2D.