The evolution of ketone body metabolism and hypoxia tolerance

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The long-term goal of my research is to understand how vertebrates respond to environmental stress through changes in substrate use and mitochondrial function. In particular, I am interested in understanding the evolution of the hypoxic response and the capacity for mitochondrial ketone body metabolism to protect against hypoxic damage. My goals for this proposal are to use a comparative approach to test the following hypotheses: Theme 1) Ketone body metabolism protects high energy tissues (brain, heart) from the oxidative stress associated with lipid metabolism. (HQP: 1 MSc and 5 BSc students over 5 years). Experiments in this theme will compare highly active (heart, brain) vs. less active (resting muscle) tissues from elasmobranchs, sturgeon and teleost fish to understand how different tissues using ketone bodies to generate ATP can protect against oxidative stress versus those using lipids. Theme 2) Chronic hypoxia will cause a whole animal ketogenic response (HQP: 1 MSc and 5 BSc over 5 years). Experiments in this theme will determine metabolic fuel use during chronic hypoxia in elasmobranchs, sturgeon and teleost fish, and test whether there is a ketogenic response in these animal groups. The metabolic profiles will be correlated to whole animal measures of hypoxia tolerance. Theme 3) Ketone body metabolism is both part of, and regulates, the hypoxic response (HQP: 5 BSc. over 5 years). We currently have little information on potential pathways for regulating ketone body metabolism in fish, or on their potential role in the hypoxic response. Experiments in this theme will seek to identify the regulatory mechanisms controlling ketogenesis, and the role of ketone bodies in facilitating the hypoxic response in various tissues. Training Impact: HQP will gain highly sought transferable skills applicable to a broad range of evidence-based careers. Students will be equipped with skills in project management, critical thinking and problem solving, data management and analysis, and effective presentation skills. Through engagement with my collaborators, HQP will understand the benefits of interdisciplinary collaboration and gain the skills to foster working relationships. Scientific Impact: Hypoxic dead zones and oxygen minima zones are increasing in extent and duration globally. Coastal systems are impacted heavily by nutrification that drives down dissolved oxygen, while increasing temperature further exacerbates this issue. Research on mitochondrial physiology of aquatic organisms will help to understand the evolution of energy production in aquatic species, and will also help us to predict how these species may respond to climate change and the predicted increase in aquatic hypoxia. Species specific information will help inform ecological changes within ecosystems and understand why some organisms are outperforming others.