The nature and significance of metabolic suppression in mammalian hibernation

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My research will help us to understand how hibernators are able to survive cold winters by reducing their rate of metabolism.**Endotherms, such as mammals and birds, use heat derived from internal metabolism to maintain high and constant body temperatures near 37C. When exposed to cold most endotherms increase metabolism, for example by shivering or activating brown adipose tissue. This strategy maintains high body temperatures in cold environments, but requires a great deal of food to power the high rates of metabolism. In contrast small hibernators, such as ground squirrels, marmots and some bats, allow their body temperatures to fall close to freezing, and metabolic rate to decrease by over 90%. This strategy conserves energy over the cold winters when food is scarce. For example, the ground squirrels that we study do not eat throughout the winter, and survive using only the fat stored within their bodies.**My research team discovered that during hibernation the activity of mitochondria - cellular structures that consume oxygen to produce chemical energy and generate heat - is reduced by up to 70% in liver, skeletal muscle and cardiac muscle. The research proposed in this grant application will determine exactly when this metabolic suppression occurs and in what tissues. It will also identify which components of mitochondrial metabolism are suppressed, and by what mechanisms. We will also evaluate potential effects of global climate change on hibernator metabolism and energy stores.**Our recent research showed that mitochondrial metabolism is suppressed very early as animals enter into hibernation, before body temperature falls from 37C to 30C. Using heart rate as an indicator, we will sample liver mitochondria when whole-animal metabolism begins to decline early in hibernation, maximizing our ability to detect important changes in mitochondrial metabolism. We will also evaluate mitochondria from brown adipose tissue, where metabolism and heat production change greatly throughout hibernation.**We will seek the molecular mechanisms responsible for this mitochondrial metabolic suppression using integrating sphere spectroscopy equipment available only at the US National Institutes of Health. These studies will also suggest what signals within the animal trigger the reduction in metabolism as animal enter hibernation. We will use these signals to attempt to induce metabolic suppression in mitochondria from non-hibernating animals, leading to practical applications. Finally, we will examine the effects of rising winter temperatures on hibernation patterns, metabolism and energy stores by varying the environmental temperature at which ground squirrels hibernate under controlled conditions.**These discovery-based studies will advance fundamental science, but also have the potential to contribute significantly to clinical and applied science. Understanding how hibernators reversibly decrease mitochondrial metabolism will further our understanding of this fascinating biological phenomenon and our knowledge of metabolic regulation. Understanding how mitochondrial metabolism can change so dramatically in a natural model will be useful for our understanding of diseases involving mitochondrial dysfunction. Successfully inducing metabolic suppression in mitochondria from a non-hibernator would be a major step towards reducing the metabolism of organs used in transplants, prolonging their viability. Understanding how rising temperatures affect hibernation metabolism will inform conservation biologists and policy-makers about potential consequences of global climate change to winter survival and geographic distribution of hibernators. In addition, I will train at least 6 graduate students who will continue to contribute to Canadian society.