Investigating the Molecular Mechanisms of Mitochondrial Calcium Uptake in Caenorhabditis elegans

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PROJECT SUMMARY The enormous societal burden caused by neurodegenerative disorders, stresses the importance of determining the underlying pathological mechanisms that promote disease. Both deregulated calcium signaling and disrupted mitochondrial function are a common symptom observed in neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. However, the underlying role these defects have in mediating pathology and if they impact each other to promote disease is not fully understood. In addition to their role in energy production, mitochondria function to sequester large influxes of cytosolic calcium and act as an organellular calcium buffer. However, the influx of calcium into the mitochondrial also stimulates the activity of the mitochondria, such as the tricarboxylic acid cycle, oxidative phosphorylation, the production of reactive oxygen species, and it can also trigger cell death. The phylogenetically conserved mitochondrial calcium uniporter complex mediates the uptake of calcium into the mitochondria. With the recent molecular identification of mitochondrial calcium uniporter complex components, many current studies have implicated altered mitochondrial calcium homeostasis as having a fundamental role in promoting neurodegeneration. These data highlight the importance of understanding the mechanisms that mediate mitochondrial calcium homeostasis. Here, we propose to utilize the genetic amenability and simplicity of C. elegans to 1) interrogate the role of the four core components of the mitochondrial calcium uniporter complex in an in vivo model system to establish a foundation of mitochondrial calcium uniporter complex function and to 2) discover new gene products that are involved in mitochondrial calcium influx. From these studies, our goals are to improve our understanding of mitochondrial calcium uptake and homeostasis and to provide critical guidance for the development of novel therapeutic strategies for treating neurodegenerative diseases.