Cellular Signaling Networks Governing Metabolic and Stress Responses

Abstract

The combined effect of metabolic and stress-response signaling networks is necessary to maintain cellular homeostasis. The metabolic networks that are based on insulin, AMPK, and mTOR pathways monitor nutrient and energy conditions to mediate anabolic or catabolic programs. There are stress-response mechanisms, such as the NRF2 antioxidant, HIF-1a hypoxic, and UPR proteolytic pathways, which respond to and counteract a particular insult to the cellular integrity. More importantly, such systems are not compartmentalized but extensively crosstalk, constituting a single adaptive network. Signals are incorporated by key hubs such as the AMPK and mTOR, switching the cell between growth and survival state. Examples of this type of integration include metabolic pathways that have a direct effect on the responses to stress, including glutamine metabolism to support antioxidant defense and lipid peroxidation to support ferroptosis. The network is the basis of significant pathologies when maladaptively regulated: the overload of the network by chronic nutrient excess causes the formation of the metabolic syndrome; the cancer cell intrudes into the normal routes of metabolism and stress adaptation, becoming cancerous; a vicious circle of metabolic failure and neurotoxic stress appears in the neurodegenerative diseases. An approach that should be used to decipher this complexity is systems biology, using omics data and computational modeling to track network interactions and predict behaviors. It was described through this network perspective that therapeutic approaches need to shift away at targeting individual molecules to perturbing key nodes and edges in the network to provide a promising platform to address complicated diseases such as diabetes, cancer, and neurodegeneration.