Mechanisms of mitochondrial-ER communication during dietary and thermal induced stress

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Project Summary/Abstract Obesity is a pandemic affecting 40% of the population that increases the risk of serious metabolic diseases including type 2 diabetes and severe forms of SARS-CoV2 infection. Obesity reduces insulin sensitivity and dysregulates glucose homeostasis sustaining high blood glucose levels and the development of type 2 diabetes. Activation of brown adipocytes (BAs) is a promising approach to treat obesity and associated diseases. Brown adipocytes rely on an extensive network of mitochondria that increases energy expenditure and maintains glucose homeostasis through glucose, amino acid, and fatty acid oxidation. During fat-induced stress, mitochondrial-endoplasmic reticulum (ER) communication sustains cellular function in BAs. However, the mechanisms by which mitochondrial-ER communication shapes cellular adaptation during obesity are poorly understood. Therefore, studying these pathways will provide new therapeutical approaches to target obesity. The main goal of this application is to study the mechanisms of mitochondrial-ER communication that ensure mitochondrial function and cellular homeostasis during diet-induced stress. We have described that in BAs mitochondrial-ER communication promotes thermogenesis during cold stimulation through the ER-resident kinase PERK. To follow up this work, in Aim 1, the effects of long-term high fat diet (HFD) will be studied in UCP1-Cre PERK-/- mice exposed to different dietary and bioenergetic conditions. Our preliminary information suggests that PERK may be signaling to the chaperone PPID to control mitochondrial protein import. In Aim 2, structural approaches using Cryogenic Electron Microscopy (CryoEM) will be used to explore the molecular interactions that control and maintain mitochondrial functions in BAs including mitochondrial protein import, focusing on PPID-dependent pathway, and cellular respiration during dietary and thermal stress. Finally, in Aim 3 the role of PPID in physiology and cellular functions will be studied in mice exposed to diet and thermal stress. While Aims 1 and part of 2 will be completed during the training stage, part of Aim 2 and the entire Aim 3 will be conducted during the independent phase of the award. The extensive training in different fields proposed in this application including physiology and cellular and structural biology will provide the tools to become an independent researcher and study the mechanisms of inter- organalle communication that regulate mitochondrial biogenesis and cellular metabolism. This training will be received in the vibrant scientific communities of Dana-Farber Cancer Institute and Harvard Medical School. This environment will expose me to the collaborations and discussions necessary for career development and future opportunities. Dr. Puigserver mentorship will be supportive to establish those connections and actively guide me in talk and manuscript preparation, student mentorship, experimental design, and career development. Together, the research and career development plans proposed in this application will strengthen my skills and competitiveness to become an independent researcher at a major institution.