Metabolic sensing by p53: Keeping the balance between life and death

There is no life without stress, and there is no life without mechanisms for adaptation to stress. Stress perturbs the balance of a living system, thereby scrutinizing the plasticity of its regulatory networks. These networks shape the composition and behavior of living systems. Biological networks serve the adaptability of the whole system, wherein multiple sensors and effectors cooperate to achieve maximal efficiency. Such interlacing cooperation needs to be controlled in relays (effectors) that integrate incoming signals and direct outgoing signals. The list of such powerful cellular effectors is short. In multicellular organisms, proteins of the p53 family (1) are well-studied examples of such effectors; as transcriptional factors, they balance the regulation of cell fate between proliferation, differentiation, and death. p53 is a relatively short-lived protein whose stability is regulated by multiple counteracting mechanisms targeting p53 to, or preventing it from, ubiquitin-dependent (2) or -independent (3) proteasomal degradation. The article by Khutornenko et al. (4) in PNAS reports a surprising connection between p53 stabilization (activation) in cancer cells and mitochondrial function. The mitochondrion is a versatile enzymatic engine that senses the metabolic requirements of cells and utilizes biochemical pathways in accordance with the cells’ proliferative or differentiation status or with a normal or transformed state. Regulation of mitochondrial activity in transformed cells also requires adaptation to changing aerobic and anaerobic conditions depending on energy supply through blood vessels and metabolic symbiosis in tumor cells (5). Because many metabolic pathways intersect in mitochondria, and because some of them directly rely on electron flow through the electron transport chain (ETC) (e.g., de novo pyrimidine synthesis), the communication between this organelle and the cell nucleus is essential. The cross-talk between these organelles has been best studied in yeast. During retrograde response (RTG) (6), for example, three proteins, Rtg2 (sensor) and Rtg1/Rtg3 (transcription factor heterocomplex), …