Regulation of mitochondrial fatty acid synthesis in the control of mitochondrial metabolism.

Project Summary Lipids are important cellular macromolecules that form membranes, are a major form of energy storage, play crucial roles in cell signaling, and are frequently dysregulated in disease. Cells obtain lipids in two main ways: either through uptake from exogenous sources or else via synthesis from acetyl-CoA in the cytoplasm by Fatty Acid Synthase (FASN). However, cells have evolutionarily maintained a second, completely distinct fatty acid synthesis pathway in the mitochondria (mtFAS). Mitochondria are well known as the “powerhouse of the cell.” In direct contrast to this well-known function, the mtFAS pathway uses acetyl-CoA to build fatty acids instead of breaking them down. Why mitochondria harbor a pathway that builds fatty acids, especially given that mitochondria take up lipids from other areas of the cell, is incompletely understood. In fact, mtFAS is so understudied that the genes encoding several steps in the pathway are still unannotated. The major goal of my research group is to define the basic biology of the mtFAS pathway. I previously defined a mechanism whereby mtFAS coordinates three major functions of the mitochondria: the TCA cycle, electron transport chain assembly, and iron-sulfur cluster biogenesis. We hypothesize that this coordinating function of mtFAS provides cells with a means to monitor mitochondrial acetyl-CoA – the substrate of the pathway – and to adjust mitochondrial metabolism accordingly. The mechanisms that regulate this nutrient sensing function and mtFAS activity in general are undescribed. The studies planned in this proposal will address crucial gaps in our understanding of how genes and metabolites control mtFAS pathway activity. We will also explore cell-type specificity of mtFAS pathway action, and the role of mtFAS in cellular differentiation signaling and cell fate decisions. Defining how mtFAS regulates mitochondrial function in response to changes in metabolite availability will rewrite the field’s working model of how mitochondria sense nutrients and adapt to changing nutritional environments. I am well suited to achieve these goals due to my expertise in mtFAS pathway function and my prior research experience in mitochondrial biology, which lies at the intersection of bioenergetics, cell signaling, and metabolic regulation. Successful completion of these studies will place me and my trainees at the forefront of the field of mitochondrial metabolism, and well-position my laboratory for long-term success.