Periodic Reporting for period 4 - OXYGEN SENSING (Acute oxygen sensing and oxygen tolerance in C. elegans)
Reporting period: 2023-07-01 to 2024-12-31
Oxygen (O2) is essential for life, and animals have evolved diverse strategies to cope with fluctuations in O2 availability. While some species thrive in O2-rich environments, others—such as high-altitude dwellers, subterranean species, and aquatic organisms—have developed remarkable tolerance to low O2 (hypoxia). In contrast, the human brain is highly sensitive to O2 deprivation, with even brief interruptions leading to severe neurological damage. To survive under varying O2 levels, animals have developed intricate mechanisms that allow them to detect and respond to both sudden drops and prolonged shortages of O2. However, despite extensive research, the molecular and neural pathways underlying acute O2 sensing and long-term survival in low-O2 conditions remain poorly understood.
This project investigates how animals sense and adapt to O2 deprivation using the roundworm Caenorhabditis elegans, a well-established genetic model organism for studying O2 sensing. C. elegans not only responds acutely to rapid drop in O2 tension but also displays extreme tolerance to O2 deprivation, making it an ideal system for uncovering the molecular mechanisms underlying acute O2 sensing and hypoxia tolerance. Our research has revealed a critical role for cGMP and neuropeptide signaling in the acute response to hypoxia, and we have elucidated how a conserved potassium channel, along with other key molecules, protects organisms from challenges such as oxidative stress and O2 deprivation. Building on these findings, we are now investigating whether these mechanisms are conserved in mammals, aiming to derive general and conserved principles underlying acute hypoxia sensing and low O2 tolerance.
Understanding how organisms respond to O2 deprivation has broad implications for human health. Conditions such as cancer, cerebral hemorrhage, and ischemia/reperfusion involve severe O2 shortages that can have catastrophic consequences. By elucidating the fundamental mechanisms of acute hypoxia sensing and low O2 tolerance, our findings could contribute to the development of new therapeutic strategies for these conditions, ultimately improving treatment options and patient outcomes.
This project investigates how animals sense and adapt to O2 deprivation using the roundworm Caenorhabditis elegans, a well-established genetic model organism for studying O2 sensing. C. elegans not only responds acutely to rapid drop in O2 tension but also displays extreme tolerance to O2 deprivation, making it an ideal system for uncovering the molecular mechanisms underlying acute O2 sensing and hypoxia tolerance. Our research has revealed a critical role for cGMP and neuropeptide signaling in the acute response to hypoxia, and we have elucidated how a conserved potassium channel, along with other key molecules, protects organisms from challenges such as oxidative stress and O2 deprivation. Building on these findings, we are now investigating whether these mechanisms are conserved in mammals, aiming to derive general and conserved principles underlying acute hypoxia sensing and low O2 tolerance.
Understanding how organisms respond to O2 deprivation has broad implications for human health. Conditions such as cancer, cerebral hemorrhage, and ischemia/reperfusion involve severe O2 shortages that can have catastrophic consequences. By elucidating the fundamental mechanisms of acute hypoxia sensing and low O2 tolerance, our findings could contribute to the development of new therapeutic strategies for these conditions, ultimately improving treatment options and patient outcomes.
This project investigates how animals detect and respond to changes in O2 availability, focusing on acute hyperoxia sensing (IL-17 signaling), acute hypoxia sensing, and anoxia tolerance. Using C. elegans as a model system, we identified genetic and molecular mechanisms that regulate O2 adaptation, revealing previously uncharacterized pathways that integrate transcriptional regulation, metabolism, and mitochondrial and lysosomal signaling.
IL-17 signaling is best known for its role in immune responses. Our work demonstrates that it is involved in a variety of cellular processes such as acute hyperoxia (~21%) responses, stress adaptation and cellular homeostasis in C. elegans. We mapped the transcriptional network downstream of IL-17 signaling, identifying key transcription factors and co-regulators that control gene expression in response to IL-17 pathway activation. By combining genetic analysis with transcriptomic profiling, we uncovered a set of IL-17 signaling regulators, including nuclear hormone receptors, transcriptional coactivators, and chromatin modifiers. These factors act together to modulate lipid metabolism, lysosomal activity, and cellular stress responses. Notably, the nuclear hormone receptor plays a central role in coordinating gene expression changes downstream of IL-17. These findings suggest that IL-17 signaling fine-tunes metabolic and stress-response pathways, providing a link between immune-like signaling and cellular adaptation processes.
In addition to our interest in hyperoxia responses, our research focuses on identifying the molecular and neural mechanisms underlying acute detection of low O2 in C. elegans. We found that exposure to hypoxia (~1%) triggers a rapid behavioral response, which is regulated by a network of sensory neurons, neuropeptides, and intracellular signaling pathways. Through genetic screening, we identified several key regulators of acute hypoxia responses, including G-protein-coupled receptors (GPCRs), cyclic nucleotide signaling molecules, and mitochondrial components. A major discovery was that cGMP signaling interacts with mitochondrial ROS to modulate O2 sensing, highlighting a pivotal role of metabolic signals in hypoxia detection. Further investigations revealed several additional key molecules, including K+ channels and H2S synthesizing enzymes, involved in acute hypoxia sensing. The identification of these molecules allows us to map the signal transduction from mitochondrial ROS to the membrane K+ channels upon acute drop of O2, addressing a long-standing puzzle in acute sensation of hypoxia.
Unlike hypoxia sensing, which requires rapid behavioral adaptations, surviving anoxia (complete oxygen deprivation) depends on long-term metabolic and physiological adjustments. Our research identified key transcription factors and metabolic regulators that contribute to anoxia resistance. These transcription factors control gene expression that are critical for animals to survive under extremely low O2 conditions, while a conserved potassium channel protects against anoxia-induced damage by maintaining cellular ion homeostasis and sustaining glycogen storage.
Our research on O2 sensing and anoxia tolerance in C. elegans sheds light on the fundamental mechanisms governing cellular responses to low O2. These findings contribute to a broader understanding of hypoxia adaptation, metabolic regulation, and stress responses across biological systems.
IL-17 signaling is best known for its role in immune responses. Our work demonstrates that it is involved in a variety of cellular processes such as acute hyperoxia (~21%) responses, stress adaptation and cellular homeostasis in C. elegans. We mapped the transcriptional network downstream of IL-17 signaling, identifying key transcription factors and co-regulators that control gene expression in response to IL-17 pathway activation. By combining genetic analysis with transcriptomic profiling, we uncovered a set of IL-17 signaling regulators, including nuclear hormone receptors, transcriptional coactivators, and chromatin modifiers. These factors act together to modulate lipid metabolism, lysosomal activity, and cellular stress responses. Notably, the nuclear hormone receptor plays a central role in coordinating gene expression changes downstream of IL-17. These findings suggest that IL-17 signaling fine-tunes metabolic and stress-response pathways, providing a link between immune-like signaling and cellular adaptation processes.
In addition to our interest in hyperoxia responses, our research focuses on identifying the molecular and neural mechanisms underlying acute detection of low O2 in C. elegans. We found that exposure to hypoxia (~1%) triggers a rapid behavioral response, which is regulated by a network of sensory neurons, neuropeptides, and intracellular signaling pathways. Through genetic screening, we identified several key regulators of acute hypoxia responses, including G-protein-coupled receptors (GPCRs), cyclic nucleotide signaling molecules, and mitochondrial components. A major discovery was that cGMP signaling interacts with mitochondrial ROS to modulate O2 sensing, highlighting a pivotal role of metabolic signals in hypoxia detection. Further investigations revealed several additional key molecules, including K+ channels and H2S synthesizing enzymes, involved in acute hypoxia sensing. The identification of these molecules allows us to map the signal transduction from mitochondrial ROS to the membrane K+ channels upon acute drop of O2, addressing a long-standing puzzle in acute sensation of hypoxia.
Unlike hypoxia sensing, which requires rapid behavioral adaptations, surviving anoxia (complete oxygen deprivation) depends on long-term metabolic and physiological adjustments. Our research identified key transcription factors and metabolic regulators that contribute to anoxia resistance. These transcription factors control gene expression that are critical for animals to survive under extremely low O2 conditions, while a conserved potassium channel protects against anoxia-induced damage by maintaining cellular ion homeostasis and sustaining glycogen storage.
Our research on O2 sensing and anoxia tolerance in C. elegans sheds light on the fundamental mechanisms governing cellular responses to low O2. These findings contribute to a broader understanding of hypoxia adaptation, metabolic regulation, and stress responses across biological systems.
Our research represents a significant step forward in the understanding of O2 adaptation mechanisms, uncovering rapid sensory mechanisms and metabolic strategies that help organisms adapt to both acute hypoxia and prolonged O2 deprivation. The intriguing discoveries made in this study have the great potential to redefine our understanding of O2 sensing. In particular, elucidating how mitochondrial activity is coupled with the second messenger in response to a sudden drop of O2 tension defines the missing link between the potential O2 sensor and the membrane potassium channels and sheds light on the fundamental mechanism of how the sensory signals are propagated within the cell to generate appropriate responses. In addition, the identification of conserved transcription factors and ion channels involved in anoxia tolerance, as well as the contribution of IL-17 signaling in cellular responses to stress conditions, offers a deeper understanding of how cellular homeostasis is maintained under prolonged O2 deprivation and other stress conditions. These findings could inform the development of novel approaches to protect cells from O2 deprivation-induced damage, with potential applications in diseases involving disrupted O2 supply, such as ischemia/reperfusion injuries.
Overall, our work bridges molecular biology, neurobiology, and metabolism, offering fresh perspectives on how organisms detect and respond to environmental stressors, particularly to low O2 exposure. By unveiling new mechanisms and pathways, we are paving the way for future research that could not only enrich basic biological knowledge but also have significant implications for understanding O2-related disorders.
Overall, our work bridges molecular biology, neurobiology, and metabolism, offering fresh perspectives on how organisms detect and respond to environmental stressors, particularly to low O2 exposure. By unveiling new mechanisms and pathways, we are paving the way for future research that could not only enrich basic biological knowledge but also have significant implications for understanding O2-related disorders.