"Rheostatic" regulation of mitchondrial volume density: evaluating the relative contributions of synthetic and degradative pathways to total organelle content.

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Mitochondria are organelles that have numerous functions crucial to cellular homeostasis. To fulfill these varied functions, mitochondria occupy a fixed percentage of the total cell volume, a parameter known as mitochondrial content. While ~2-20 fold variations in mitochondrial content are observed across the tissues of higher eukaryotes, the developmental program that establishes these "set points" is unknown. Equally unclear is what limits the adaptive responses of the organelle in select tissues upon exposure to a given physiological stimulus. My NSERC Discovery program will address these two fundamental biological problems by testing the following hypothesis; inter-tissue differences in both total mitochondrial content and its adaptive potential are explained by the differential regulation of flux through pathways that synthesize and degrade the organelle. An integrative, multifaceted approach will be used to quantify total mitochondrial content in different tissues of C57BL/6 mice, and measure the relative contributions of organelle biogenesis and turnover in regulating these "set points", both under basal conditions and during physiological transitions. Mechanisms that regulate the activities of relevant synthetic and degradative pathways will also be investigated, first in situ in primary cultures and then in vivo in the whole animal. Initially, these studies will be focused on the their involvement in regulating mitochondrial content in the liver; however, over the long-term, they will be expanded to include other tissues of C57BL/6 mice, as well as those of transgenic mice with isolated defects in organelle biogenesis and turnover, so that the inter-tissue nature of the hypothesis can be fully addressed. Numerous training opportunities for highly qualified personnel exist within the outlined program, whose advancement will make fundamental contributions to our understanding of biology by identifying the molecular genetic mechanisms that regulate mitochondrial content and determining whether they are conserved across tissues.