Turning the Oxygen Dial: Balancing the Highs and Lows

Molecular oxygen is an essential substrate in mammalian metabolism. Imbalances in oxygen levels are associated with a wide range of conditions in human health and disease. The Jumonji C domain histone lysine demethylases, KDM5A and KDM6A, are recently discovered oxygen sensors that regulate demethylation and cellular differentiation. Some animals are tolerant of extreme hypoxia and have developed unique adaptations that might have relevance to oxygen sensing and adaptation in humans. Hypoxia can have both beneficial and toxic effects depending on the severity and duration of hypoxia, in combination with cell- and tissue-specific metabolic demands. In a mouse model of pediatric mitochondrial disease, hypoxia itself, but not activation of the hypoxia transcriptional factor (HIF) response, is sufficient to rescue disease. Decreased tissue oxygen consumption and resulting excess oxygen contributes to pathology, which can be reversed with normalization of oxygen levels by hypoxia. Preclinical and early clinical studies demonstrate that hypoxia or manipulation of the hypoxia response can potentially be used to treat various diseases, including mitochondrial diseases, neurodegenerative and cardiovascular diseases, anemia, and malignancies, among others. Oxygen is both vital and toxic to life. Molecular oxygen is the most used substrate in the human body and is required for several hundred diverse biochemical reactions. The discovery of the PHD-HIF-pVHL system revolutionized our fundamental understanding of oxygen sensing and cellular adaptations to hypoxia. It deepened our knowledge of the biochemical underpinnings of numerous diseases, ranging from anemia to cancer. Cellular dysfunction and tissue pathology can result from a mismatch of oxygen supply and demand. Recent work has shown that mitochondrial disease models display tissue hyperoxia and that disease pathology can be reversed by normalization of excess oxygen, suggesting that certain disease states can potentially be treated by modulating oxygen levels. In this review, we describe cellular and organismal mechanisms of oxygen sensing and adaptation. We provide a revitalized framework for understanding pathologies of too little or too much oxygen. Oxygen is both vital and toxic to life. Molecular oxygen is the most used substrate in the human body and is required for several hundred diverse biochemical reactions. The discovery of the PHD-HIF-pVHL system revolutionized our fundamental understanding of oxygen sensing and cellular adaptations to hypoxia. It deepened our knowledge of the biochemical underpinnings of numerous diseases, ranging from anemia to cancer. Cellular dysfunction and tissue pathology can result from a mismatch of oxygen supply and demand. Recent work has shown that mitochondrial disease models display tissue hyperoxia and that disease pathology can be reversed by normalization of excess oxygen, suggesting that certain disease states can potentially be treated by modulating oxygen levels. In this review, we describe cellular and organismal mechanisms of oxygen sensing and adaptation. We provide a revitalized framework for understanding pathologies of too little or too much oxygen. in the atmosphere, defined as less than 21% oxygen. Hypobaric hypoxia results from decreased barometric pressure (e.g., high altitude). Normobaric hypoxia results from decreased inspired fraction of oxygen (FiO2). alternating episodes of normoxia and hypoxia, leading to cyclical bursts of deoxygenation and reoxygenation. Intermittent hypoxia is a feature of obstructive sleep apnea and central sleep apnea. severe hypoxia or anoxia (complete lack of oxygen), coupled with reduced availability of nutrients, including glucose, fatty acids, amino acids, and vitamins. In tissues, ischemia results from inadequate blood flow due to arterial blood flow restriction, leading to accumulation of metabolic waste products, cellular dysfunction, and tissue damage. the Michaelis constant value at which the substrate concentration permits a reaction rate that is half of Vmax, the maximum rate of an enzymatic reaction when saturated by the substrate. Enzymes with high KM have low affinity for their substrates. As an example, PHD proteins have low oxygen affinities (high KM), enabling them to sense oxygen in physiological ranges. the partial pressure of oxygen (PO2). The partial pressure of oxygen at sea level is 21% of the standard atmospheric pressure of 760 mmHg, equivalent to 160 mmHg. At sea level, Earth’s atmosphere is composed of 78% nitrogen, 21% oxygen, 0.9% argon, 0.03% carbon dioxide, and trace amounts of other gases.