Mitochondrial Regulation of Calcium Signaling in C. elegans

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The nematode Caenorhabditis elegans expresses a rhythmic behavior whose timing is controlled by oscillatory Ca2+ signaling. The behavior is anatomically simple, with the intestine, several muscle cells, and two neurons communicating to establish the defecation motor program (DMP). The posterior cells of the intestine are the behavioral pacemaker, and the canonical signaling cascades that regulate basal, rhythmic Ca2+ oscillations in these cells have been well-characterized. However, these oscillations also help to set metabolic homeostasis and are coupled to ion transport processes that facilitate nutrient uptake. The research supported by this award will allow us to identify the underlying mechanisms through which these processes are integrated, focusing in particular on the metabolic hub of the cell, the mitochondria. The main function of mitochondria is to transduce energy through oxidative phosphorylation, a process which generates most of the endogenous ROS in cells. However, mitochondria are also well-recognized to contribute to Ca2+ signaling by buffering Ca2+. Recent groundbreaking work has uncovered novel molecular mechanisms that contribute to Ca2+ uptake by mitochondria, to maintaining organelle-specific protein homeostasis, and to signaling through ROS. Each of the aims in this study is intended to query these specific aspects of mitochondria's function with respect to their effect on oscillatory Ca2+ signaling. We will investigate the role of mitochondrial Ca2+ uptake, the mitochondrial unfolded protein response (UPRmt) and mitochondrial reactive oxygen species (ROS) generation in maintaining behavioral rhythmicity and metabolic homeostasis. The project will include training and research opportunities for under-represented minority students. Furthermore, a new K-12 learning program will be developed and led by a former postdoctoral trainee from the lab who comes from an under-represented background and has extensive experience in this area. A website will also be developed and expanded to facilitate communication with the stakeholder community and to disseminate teaching modules developed through our learning program. Results will be disseminated through publication, but the underlying data sets will be made freely available upon request. Useful c. elegans strains developed during the course of the project will be made publically available through the C. elegans Genetics Consortium (http://www.cbs.umn.edu/research/resources/cgc). Novel plasmids and molecular biological reagents will be handled by Addgene (https://www.addgene.org/).