Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis

Virtually all cells exhibit metabolic flexibility and are capable of shifting their reliance on glycolysis relative to mitochondrial respiration. Such shifts can occur at different timescales through a variety of mechanisms, allowing cells to cope with prevailing nutrient availability or energetic demands. There is mounting evidence of the therapeutic potential of targeting such shifts. For example, many cancer cells rely on aerobic glycolysis (the Warburg effect)1, and a recent study has shown that pharmacological agents that shift their metabolism toward mitochondrial respiration can retard tumor growth2. Conversely, studies in animal models have shown that attenuating mitochondrial respiration can prevent the pathological consequences of ischemiareperfusion injury in myocardial infarction and stroke3–7. 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 hypoxia9,10. HIF inhibitors and activators have been identified through both academic and pharmaceutical drug screens and exhibit preclinical efficacy in treating cancer11 and in ischemic disease12, respectively. Other approaches to treat ischemic injury include induced hypothermia, which has met with mixed results13. New classes of agents, that can be titrated to safely shift energy metabolism, may yet provide important therapeutic value in several human diseases. Here we use a nutrient-sensitized screening strategy to identify drugs that shift cellular energy metabolism based on their selective effect on cell growth and viability in glucoseversus galactose-containing media. Nutrient-sensitized screening is based on the evidence that mammalian cells redirect their energy metabolism in response to the available sugar source14. Culturing cells in galactose as the sole sugar source forces mammalian cells to rely on mitochondrial oxidative phosphorylation (OXPHOS) and was previously used to diagnose human mitochondrial disorders or drug toxicity15,16. By screening our chemical library for drugs that selectively inhibit cell growth and proliferation in galactoserelative to glucose-containing media, we identify several FDA-approved compounds that redirect oxidative metabolism to glycolysis. We pursue the mechanism and potential clinical utility of one drug, meclizine, which is available without prescription, crosses the blood-brain barrier and has never, to our knowledge, been linked to energy metabolism.