Dying for Something to Eat: How Cells Respond to Starvation

Abstract

Food is a requirement of life. Unicellular and multicellular organisms have therefore developed mechanisms to detect, react to and, if necessary, survive the lack of it. In mammals, responses to lack of nutrients in blood are coordinated at the organismal level by hormonal cues. However, individual cells also sense and respond to nutrient deprivation, which occurs under physiological or pathological situations such as fasting, ischemia or solid tumor development. Frequently cells try and survive nutrient deprivation by reducing their energy and carbon requirements and by recycling structural components. However, under certain conditions, the cell reacts to nutrient deprivation by engaging the mitochondrial pathway of apoptosis. Indeed, the metabolic state of the cell can regulate pro- and antiapoptotic Bcl-2 family proteins such as PUMA, Bad, Bim or Mcl-1, thus altering the response to pro-apoptotic stimuli. Severe energetic stress can also kill cells by a form of death with necrotic phenotype. Metabolic pathways are currently receiving enormous attention from cell biologists, due to the fact that tumors have a special metabolism which makes them more susceptible to lack of specific nutrients, particularly glucose and glutamine. For this reason, targeting tumor metabolism opens new therapeutic avenues. We will discuss how nutrient deprivation engages cell death pathways, and how cell metabolism interferes with the apoptotic machinery by regulating apoptotic proteins. We will also re-examine the hypothesis that ATP levels determine whether a cell dies by apoptosis or necrosis. Finally, we will discuss how and why metabolic stress can lead to either cell adaptation and survival or cell death.