Understanding mitochondria and lipids droplet interactions in cell biology

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Mitochondria are important regulators of energy homeostasis as they provide energy to many physiological processes. In lipid metabolism, mitochondria support both fatty acid utilization and synthesis. Such opposite functions require specialized mitochondria tuned to perform specific works. Moreover, these processes need to take place close to the storage unit such as the lipid droplets, where the lipids are stored. Previously, we discovered different mitochondrial subpopulations with distinct roles in brown adipose tissue. We have shown that mitochondria bound to lipid droplet, named peridroplet mitochondria (PDM), enhance lipid synthesis. Whereas the cytosolic mitochondria (CM, not bound to lipid droplets) are the mitochondria consuming lipids. The liver has also a high capacity to synthesize and to store lipids. As such, the liver acts as a major regulator of whole-body lipid metabolism in mammals. The role of mitochondria interacting with lipid droplets nor their regulation are still unknown in the liver. My proposal aims to answer these questions which will lead to expanding our understanding of how mitochondria regulate lipid metabolism in the liver. First, we will determine the function of CM vs. PDM in the liver by measuring their capacity to use lipids and glucose. We will also establish how these mitochondria regulate lipid metabolism in fasting and fed states. Next, we will assess the exact role of PDM in mice by using a viral gene delivery method to enhance specifically PDM in the liver. Using state-of-the-art proteomics approaches, we will define the proteome of CM and PDM as well as identify novel regulators. Finally, we will explore how AMPK and mTOR signaling pathways, two well-known regulatory nodes that govern lipid metabolism, control CM, and PDM. To do so, we will perform signaling studies to establish how these two pathways are regulated in hepatocytes. This will represent the first study to decipher their precise functions in the liver. Overall, our work will represent one of the very first studies exploring the mechanisms that control specialized mitochondria regulating lipid metabolism. The proposed research strategy will characterize the unique function of each of these mitochondrial population and the signaling pathways that govern mitochondria and lipid droplet interactions. This work will not only represent a breakthrough in the understanding of lipid metabolism in cell biology but will also lead to the identification of the key factors involved in mitochondria attachment to lipid droplets. As mitochondria and lipid droplets are present in most cells, the discoveries generated by this research program will be significant not only for liver metabolism but also for all organs. Following this initial proposal, our approaches will allow us to identify the key potential regulators and pursue our long-term goal to define the mitochondrial mechanisms regulating lipid and glucose metabolism.