Mitochondrial Calcium Signaling in Cell Intrinsic Immunity

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PROJECT SUMMARY The phagocytes of the immune system require a rapid burst of energy to phagocytose and kill pathogens in a timely manner. Energy demanding macromolecular complexes such as vacuolar ATPase (V-ATPase) and NADPH oxidase (NOX) complexes are recruited to the phagosome to acidify, oxidize, kill, and digest the pathogenic cargo. Reprogramming of the metabolic machinery by gene expression is too slow to meet the sharply increased demand for energy and metabolites. How do the sentinel phagocytes transmit the recognition of pathogens to switch the primary gears of cellular metabolism so rapidly? Our preliminary data indicated that the Ca2+-selective, mitochondrial ion channel, MCU, plays a crucial role in the signaling circuits that rapidly connect the sensory receptors of pathogens to the metabolic outputs necessary for phagosomal killing. Pursuing these tantalizing leads has now laid a strong scientific foundation to hypothesize that assembly of phagosome-mitochondria proximity architecture (PMPA) and mitochondrial Ca2+-signaling fuels cell-intrinsic immunity. In Aim1, we define the mechanisms underlying mitochondria-phagosome interactions triggered by C. albicans. In Aim 2, we define mechanisms through which mCa2+-signaling is regulated in activated macrophages. In Aim 3, we define the key metabolic outputs of mCa2+-signaling that drive microbial killing. This research is conceptually innovative because it unravels fascinating new connections between pathogen mitochondrial physiology, immunometabolism and microbial killing. Innovations include tools to monitor mCa2+-elevations in primary macrophages executing phagocytosis and Electron Tomography based 3D reconstructions of Mitochondria-Phagosome interactions. The research has the potential to reveal design principles that are of salience to other specialized phagocytic processes such as clearance of apoptotic cells, toxic debris, and synaptic pruning. From a translational/preclinical perspective, our findings may reveal novel molecular targets and pathways for new immunomodulatory therapies.