Tissue-specific roles of mitochondrial dynamics in stress resistance and longevity

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Mitochondria are a part of the cell that is responsible for the production of energy. Mitochondria also perform several other critical functions within the cell and are essential for life in most organisms. While mitochondria have been shown to influence aging, the relationship between mitochondrial shape, mitochondrial function and longevity is poorly defined. Under normal conditions, mitochondria are dynamic organelles: they continuously split off of larger mitochondrial networks, in a process known as mitochondrial fission, and rejoin those networks, in a process known as mitochondrial fusion. Combined these processes are known as mitochondrial dynamics. Experiments in a genetic model organism called C. elegans have shown that decreasing mitochondrial fission can lead to increased lifespan. Since similar observations have been made in yeast, and decreased mitochondrial fragmentation has been associated with longevity in long-lived human centenarians, this suggests that altering mitochondrial shape in order to form larger mitochondrial networks can increase longevity, and that this response is conserved across species. Currently, the mechanism by which altering mitochondrial dynamics can influence longevity is not known. Furthermore, the role of mitochondrial dynamics in an organism's response to stress, and how this might contribute to lifespan, is incompletely defined. We hypothesize that decreasing mitochondrial fragmentation increases lifespan through alterations in mitochondrial function. We further hypothesize that increasing an organism's capacity for fission and fusion through the simultaneous overexpression of fission and fusion proteins will increase mitochondrial health and longevity. To test these hypotheses, we will use C. elegans models to define the contribution of mitochondrial dynamics to stress resistance and longevity through the completion of two research projects. In Project 1, we will determine how different types of stress affect mitochondrial shape and how changing mitochondrial shape affects stress resistance. In Project 2, we will also define the conditions under which changes in mitochondrial dynamics can increase lifespan and explore the underlying mechanisms. By using C. elegans, we are able to examine mitochondrial morphology in a live animal, and to study the effect of modulating mitochondrial dynamics on whole organism phenotypes such as stress resistance and lifespan. Defining the relationship between mitochondrial dynamics, stress resistance and longevity, and elucidating the underlying mechanisms, will advance our knowledge about the role of mitochondrial morphology and function in aging and resistance to stress. Overall this work will increase our understanding of the aging process.