LAUSR

Origins and evolution of hypoxia response In our current oxygen-rich atmosphere, the ability of eukaryotic cells to sense variation in oxygen concentrations is essential for adapting to low-oxygen conditions. However, Earth's atmosphere has not always contained such high oxygen concentrations. Hammarlund et al. discuss oxygen-sensing systems across both plants and animals and argue that the systems are functionally convergent and that their emergence in an initially hypoxic environment shaped how they operate today. Science, this issue p. eaba3512 BACKGROUND Animals and land plants are the most diverse complex multicellular life-forms on Earth, and their success intricately links a capacity for adhering cells to perform different tasks at different times. The performance of cell tasks, however, can be both dependent on and challenged by oxygen. Oxygen acts as the final electron acceptor for aerobic respiration but also participates in reactions to generate metabolites and structural macromolecules; recently, oxygen also has come to the fore for its signaling role in developmental programs in animals and plants. Today, the relative oxygen concentration within multicellular organisms integrates information about cell position, metabolic state, and environmental conditions. For the rise of complex life, the capacity to link oxygen perception to transcriptional responses would have allowed organisms to attune cell fates to fluctuations in oxygen availability and metabolic needs in a spatiotemporal manner. ADVANCES Recent discoveries of oxygen-sensing mechanisms in different eukaryotic kingdoms allow us to compare molecular strategies dedicated to this task and the outputs that these produce. Remarkably, higher plants and animals converged, from a functional perspective, to recruit dioxygenase enzymes to posttranslationally modify transcriptional regulators for proteasomal degradation at the relatively “normoxic” conditions. In this way, transcriptional responses can be repressed at higher oxygen levels (which is context dependent) but are specifically elicited under hypoxia. The mitigation of the effects of prolonged hypoxia is also similar in animals and plants: reduction of metabolic rate, avoidance of toxicity of anaerobic by-products, and prevention of cell injury upon reoxygenation. Recent geological and phylogenetic investigations allow us to reconstruct the origin of such molecular switches in the eukaryotic clade and compare it with the development of organ-grade multicellularity. The results support the perspective that oxygen-consuming enzymes evolved sensory functions depending on the contingent requirements imposed by the environment and developmental programs. Considering that these sensing machineries evolved at a time (in the Neoproterozoic and early Paleozoic eras) when atmospheric oxygen concentrations were substantially lower than today, and in marine settings where redox is prone to vary, they may have played a major role in guiding development and homeostasis in response to endogenous oxygen dynamics. The broad scope of oxygen sensing and response machineries for multicellular success is further highlighted when hijacked during tumorigenesis to support uncontrolled growth in a variety of conditions and stresses. OUTLOOK The broad role of oxygen-sensing systems in the survival and evolution of complex multicellular life requires further exploration, including into the commonality and conservation of the oxygen-sensing machineries. That higher plants and animals adopted alternative solutions to direct their primary hypoxia responses, despite their ancestors likely being equipped with the same enzymatic repertoire, may describe differences in their respective environmental, cellular, and organismal features and histories. Broadly, by shifting focus from exploring oxygen-sensing mechanisms as primarily a response to oxygen shortage for aerobic respiration, we can potentially reveal previously unidentified ways in which these systems can be manipulated for clinical and agricultural benefit. By such an approach, we will gain further insight to their broad scope and the challenges that multicellular life is exposed to, today as in geologic history. Eukaryotic kingdoms convergently recruited dioxygenases to sense fluctuations in ambient oxygen and to respond under hypoxia. Oxygen sensing allows cells to attune their metabolism and fate to spatiotemporal requirements, a critical component in complex multicellularity. The basal oxygen-sensing mechanisms use alternative targets in plants, fungi, and animals—kingdoms that alone demonstrate the capacity to form tissues of different complexities. Oxygen-sensing mechanisms of eukaryotic multicellular organisms coordinate hypoxic cellular responses in a spatiotemporal manner. Although this capacity partly allows animals and plants to acutely adapt to oxygen deprivation, its functional and historical roots in hypoxia emphasize a broader evolutionary role. For multicellular life-forms that persist in settings with variable oxygen concentrations, the capacity to perceive and modulate responses in and between cells is pivotal. Animals and higher plants represent the most complex life-forms that ever diversified on Earth, and their oxygen-sensing mechanisms demonstrate convergent evolution from a functional perspective. Exploring oxygen-sensing mechanisms across eukaryotic kingdoms can inform us on biological innovations to harness ever-changing oxygen availability at the dawn of complex life and its utilization for their organismal development.