Targeting ER-mitochondrial calcium signaling to promote healthier aging

Project Summary/Abstract Fundamental gaps remain in our understanding of the cell biological mechanisms that drive mitochondrial decline and associated age-related diseases. Organelles like the mitochondria and endoplasmic reticulum (ER) are physically and functionally linked, in part via sites of membrane contact. These lines of communication between mitochondria and other organelles represent an understudied avenue by which to therapeutically target mitochondrial function. Our long-term goal is to understand the physiological roles of inter-organelle communication during aging and age-related disease. In pursuit of that goal, our objective in this application is to determine how the ER regulates mitochondrial health during aging through its role as a platform for calcium signaling. We have exploited the simple anatomy of C. elegans and experimental advantages in genetics and microscopy to lay a foundation in this model for the study of ER-mitochondrial interactions. Similar to mammals, the worm ER calcium efflux channel, inositol triphosphate receptor (InsP3R), exerts potent control over mitochondrial bioenergetics, and we have extended the roles of InsP3R to regulation of mitochondrial gene expression and dynamics in the worm as well. Furthermore, the InsP3R regulates lifespan in C. elegans through mechanisms that depend upon mitochondrial function. Here we will test the hypothesis that ER remodeling in aging animals acts to trigger mitochondrial dysfunction and organismal decline by promoting aberrant subcellular calcium signaling and dynamics. To test this hypothesis, we will first determine whether the InsP3R is a cell autonomous regulator of mitochondrial function and lifespan. Secondly, we will identify the molecular mechanisms linking InsP3R activity to the diverse changes observed in mitochondrial behavior. Finally, we will determine how organellar remodeling of the calcium flux machineries initiates age-onset mitochondrial dysfunction. By revealing the mechanisms by which ER signaling governs mitochondrial health at the organismal level, these results will open new therapeutic avenues in treating mitochondrial pathologies.