Origins of variation in mitochondrial metabolism

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These studies help define the cellular and genetic pathways that are the underpinnings of diversity seen in nature, giving insight into the evolutionary origins of pathways known to be vital to our own metabolism. This work is done primarily to understand evolutionary origins of diversity in genes critical in determining the metabolic physiology of animals, but the results have direct relevance to the many human diseases with etiologies that are intertwined with energy metabolism, such as diabetes and ischemia/reperfusion. ***My program explores the origins and consequences of variation in muscle energy production: how muscle metabolism is remodelled when needed and how differences in metabolic machinery arise between tissues and animals as a consequence of evolution and development. By comparing and contrasting models and experimental approaches, we hope to distinguish between regulatory pathways that are broadly conserved among animals and those that are responsible for unique features of specific tissues and animals.***In the next grant cycle we take advantage of the growing database of genomic information to begin to tease apart the regulatory basis of differences in energy metabolism between groups of animals. The proximate questions focus on (i) how differences in muscle metabolic properties arise between lineages of mammals and (ii) whether the regulators that are critical in mammals are shared with primitive vertebrates. ***The first two objectives focus on a subunit of cytochrome c oxidase, the enzyme that is responsible for using most of the oxygen consumed by the animal. One subunit, COX4, is present in two forms in all vertebrates. We are building on previous studies to explain how the protein differs between mammals and less complex vertebrates. ***The second two objectives focus on PGC1, a family of proteins that regulate the expression of suites of genes encoding metabolic proteins. Its structure has evolved in ways that impart different functions in animal lineages, and thus it presents a model to study how evolution has influenced the function of this protein. ***The program is arranged in a way to support a lab focused on 4 graduate students, with additional opportunities for undergraduate summer students and Honour's thesis students. The experiments proposed will provide many training opportunities for students hoping to gain a greater understanding of the interactions between animal physiology, evolution and cell biology. All of these highly qualified personnel will gain important technical training that can be used to tackle questions in academic and industrial research.