The Functions of Mitochondrial Membrane Contact Sites in Space and Time

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Mitochondria form elaborate reticular networks that make physiologically important contacts with nearly every other organelle. Recently, mitochondrial membrane contact sites (MMCSs) have been shown to play a role in regulating mitochondrial function. Beyond physically tethering organelles, MMCSs have been implicated in interorganelle communication, modulating mitochondrial fusion and fission, and adapting the mitochondrial network to function under stress conditions. Despite progress in defining the molecular composition of individual MMCSs, little is known about the functions of MMCSs or how they are regulated in space and time. Previous studies have focused on individual MMCSs under a narrow range of biological conditions; however, multiple MMCSs exist simultaneously, creating a dynamic network that controls the function of mitochondria. Thus, defining the functions of MMCSs and dissecting how these functions are coregulated in space and time to modulate mitochondrial function represents a well-recognized gap in knowledge. To address this complex problem, this proposal will analyze the simplified MMCS network of the budding yeast Saccharomyces cerevisiae. A multidisciplinary approach will be used to characterize novel functions of the mitochondria-ER- cortex anchor (MECA) and probe how these functions are coregulated with other MMCSs to adapt the mitochondrial network to function under various stresses. MECA forms a unique tripartite organelle contact site between mitochondria, the ER, and the plasma membrane. Work in Aim 1 will determine the mechanism and function of contact between MECA and the ER and test the hypothesis that MECA-ER contacts are involved in mitochondrial respiratory function. Work in Aim 2 will use unbiased screening approaches to identify novel genes and metabolites involved in mitochondrial functions that are regulated by MECA. Work in Aim 3 will characterize the dynamic regulation of MECA and other MMCSs in response to environmental or mitochondrial stresses and test the hypothesis that MMCSs are coregulated to adapt the mitochondrial network for optimal function. This proposal will identify novel functions of MECA and describe how this contact site and others are regulated through space and time. This work will extend beyond the characterization of a MMCS in a single context and begin dissecting how MMCSs are regulated at a systems level to modulate mitochondrial function. The training plan in this proposal is designed to teach the skills required to operate as an independent researcher. The central focus will be training in interdisciplinary research and career development skills. This proposal provides the opportunity to learn state-of-the-art biochemical, genetic, and systems level approaches to ask fundamental questions about organelle biology. Scientific communication and networking skills will be strengthened by authoring scientific papers and presenting at group meetings and conferences. This proposal also provides training in mentorship, ethical research practices, and promoting diversity and inclusion in science.