Deciphering novel cell death mechanisms and metabolic reprogramming in response to microenvironmental stress.

Title: Deciphering novel cell death mechanisms and metabolic reprogramming in response to microenvironmental stress. Understanding how cells respond to microenvironmental stress is essential for unraveling fundamental biological processes. While acute stressor perturbations in tissues are often transient, the cellular changes induced can persist long after the initial stressor has subsided, challenging our current knowledge of long- term impact of microenvironmental stress. My laboratory combines cell- and genome-engineering with transcriptional, epigenetic, and metabolic profiling to understand cellular fate decisions informed by the surrounding microenvironment. With these tools, we have revealed an unexpected phenomenon: Cells exposed to immune cell activation can undergo cell death without specific antigen recognition, cytokine signaling or apoptosis induction, suggesting the existence of a novel mechanism of cell death with far-reaching implications for various biological processes. Our preliminary experiments provide a crucial insight: the disruption of translation of mitochondrial respiratory chain genes confers resistance to this form of cell death in exposed cells. This observation suggests that exposure to immune activation induces nutrient deprivation in the surrounding microenvironment, forcing exposed cells to adopt alternative metabolic pathways for survival. The absence of widespread tissue death during exposure to immune activation further supports this hypothesis, indicating that surviving cells likely undergo significant metabolic reprogramming to adapt to these challenging conditions. The research in this Maximizing Investigators' Research Award proposal aims to capitalize on our deep expertise in cell engineering and metabolic profiling to (I) characterize the precise mechanism of cell death in non-targeted cells exposed to immune activation and (II) elucidate the metabolic and subsequent epigenetic reprogramming events occurring in surviving cells, along with their long-term consequences in the contexts of wound healing, cellular senescence, and tissue homeostasis. Understanding this novel cell death mechanism and its evasion through metabolic reprogramming has the potential to revolutionize our comprehension of fundamental cellular processes. This knowledge could have profound implications for diverse fields of cell biology, shifting paradigms in our understanding of how cells respond to external stressors and commit to life-or-death fate decisions. Our findings may illuminate new principles of metabolic plasticity and cellular adaptation, providing insights into the complex interplay between metabolism, cell survival, and cell death pathways. Ultimately, this research will expand our basic understanding of cellular homeostasis, stress responses, and tissue maintenance, contributing to the broader knowledge base of cellular and molecular biology. These fundamental insights could inform future studies across various biological disciplines, potentially opening up new avenues for exploring cellular behavior in both normal and pathological states.