Metabolic cues for EMS. The basic metabolic processes occurring in all cells provide a rich tapestry of potential cues for EMS. Here, the oxidation of glucose is depicted, showing several potential EMS cues in green. Initially, a substrate is transported into the cell cytoplasm for use. In this example, glucose is brought in via GLUT transporters and then processed via the 10 reactions of glycolysis to yield two pyruvate molecules and two ATP, along with two NADH. From here, pyruvate can be fermented to lactate, which can be released from cells via monocarboxylate (MCT) transporters. Alternatively, pyruvate can be used to produce acetyl-CoA (also producing NADH and CO₂ as a byproduct) that can enter the TCA cycle in the mitochondrial matrix. The TCA cycle reduces a number of NAD⁺ molecules to NADH and FAD⁺ to FADH₂, while also generating more CO₂. The NADH and FADH₂ in turn act as electron donors to the ETC in the inner mitochondrial membrane to generate a proton gradient that ATP synthase (i.e., Complex V) uses to yield large amounts of ATP, which can then be exported via the adenine nucleotide translocator in exchange for ADP. In addition to the generated CO₂, lactate, or glucose levels themselves acting as cues, the redox state of the cell or the ATP:ADP ratio may also signal to open K⁺ channels such as K_ATP to generate membrane hyperpolarization. Either ATP:ADP ratio in the bulk cytosol or in submembrane regions around response elements could conceivably contribute to this process. The generation of these cues may occur directly in the working cells of a given tissue such as cardiac myocytes in the heart, or in metabolic sentinel cells such as in pericytes in the brain.