Sharks have an unusual physiology, which remains largely a mystery. Opposed to most bony fish, elasmobranchs are isosmotic with seawater, and do so by accumulating extremely high levels of urea as an osmolyte. As urea is chaotropic, elasmobranchs release trimethylamine N-oxide (TMAO) into bodily fluids to protect proteins from urea toxicity, as well as improving resistance to high temperatures and pressures. In addition, elasmobranchs cannot directly oxidise lipids, which are converted to ketones, that are exported to other tissues. Elevated ketones acidify the blood in mammals, and the formation of acetone results in wasted energy. Moreover, in mammals this process is accessed in hypoglycaemic states due to glucose poor diets, starvation, and severe diabetes. To date there has been no work that interdigitates the role and influence of TMAO with energy metabolism in sharks. We also know little about how ketones and TMAO contribute to stressors such as hypoxia. Using high-resolution respirometry and a novel ATP-binding fluorophore, we addressed the effect of TMAO on mitochondrial ketone, lipid, pyrimidine and carbohydrate driven respiration, and ATP production, in cerebellum and heart of anoxia-tolerant epaulette sharks exposed to normoxia and 24h hypoxia.