Discovery and Therapeutic Potential of Drugs That Shift Energy Metabolism from Mitochondrial Respiration to Glycolysis Hhs Public Access Meclizine Blunts Respiration in a Manner Distinct from Classic Inhibitors Supplementary Material

Most cells can dynamically shift their relative reliance on glycolytic versus oxidative metabolism in response to nutrient availability, during development, and in disease. Studies in model systems have shown that redirecting energy metabolism from respiration to glycolysis can suppress oxidative damage and cell death in ischemic injury. At present we have a limited set of drugs that safely toggle energy metabolism in humans. Here, we introduce a quantitative, nutrient sensitized screening strategy that can identify such compounds based on their ability to selectively impair growth and viability of cells grown in galactose versus glucose. We identify several FDA approved agents never before linked to energy metabolism, including meclizine, which blunts cellular respiration via a mechanism distinct from canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: All experiments were done in accordance with the national and institutional guidelines for animal welfare, adhering to protocols approved by the institutional subcommittee on research animal care. injury in murine models. Nutrient-sensitized screening may offer a useful framework for understanding gene function and drug action within the context of energy metabolism. Virtually all cells exhibit metabolic flexibility and are capable of shifting their relative reliance on glycolysis versus mitochondrial respiration. Such shifts can occur at different timescales via a variety of mechanisms allowing cells to cope with prevailing nutrient availability or energetic demands. There is mounting evidence that targeting this shift may hold therapeutic potential. For example, many cancer cells rely on aerobic glycolysis (termed the Warburg effect) 1 and a recent study has shown that pharmacologically shifting their metabolism towards respiration can retard tumor growth 2. Conversely, studies in animal models have shown that inhibition of mitochondrial respiration can prevent the pathological consequences of ischemia-reperfusion injury in myocardial infarction and stroke 3-7. These observations motivate the search for agents that can safely induce shifts in cellular energy metabolism in humans. Promising work in this area has focused on hypoxia inducible factor (HIF) 8 , a well-studied transcriptional regulator of genes involved in the cellular adaptation to hypoxia 9 , 10. HIF inhibitors and activators have been identified through both academic and pharmaceutical drug screens and have been shown to exhibit preclinical efficacy in cancer 11 and in ischemic disease …