An evolving body of evidence indicates that the cellular response to physiologic and pathophysiologic stress is highly attuned to the bioenergetic state of the cell, including ATP/ADP ratio and redox status (NADH/NAD). These parameters are predominantly influenced by mitochondrial fuel metabolism. Importantly, the versatility of the mitochondrial metabolome to process alternate energy substrates such as carbohydrates, fatty acids and ketone bodies may feature prominently in the manner in which cells interpret and respond to stress stimuli. The primary focus of the Danial laboratory is to delineate cellular energy and nutrient sensing pathways, including metabolic checkpoints that integrate cellular bioenergetics and cellular responses to stress, including the decision to undergo apoptosis. We employ a multi-disciplinary approach that draws on mouse genetics, mitochondrial physiology, shRNA library screens, chemical biology and proteomics to identify key mechanisms that determine the cell’s choice of energy substrates and thereby modulate cellular stress responses. The ultimate goal of this integrated approach is to uncover potential therapeutic targets in order to manipulate cellular energy metabolism in diseases such as cancer, diabetes and neurodegeneration.