Risks of perturbed oxygen homeostasis: responses and adaptations to hyperoxia and hypoxia

Oxygen utilization and hypoxia: The use of oxygen for oxidative phosphorylation in mitochondria allows the production of > 15× more adenosine triphosphate per molecule of glucose (which can be substantially more useful for the oxidation of fatty acids) as compared with oxygen-independent glycolysis. Oxygen is also required for hundreds of other biochemical reactions, as has been recently noted in a comment on the importance of oxygen homeostasis for human health.1 Aside from this great efficiency and multifunctionality, oxidative metabolism also confers substantial risks to aerobic species in conditions of unbalanced oxygen availability/demand, primarily due to disruption of the cellular redox balance and the production of highly reactive oxygen-derived molecules: reactive oxygen species. Insufficient oxygen availability (hypoxia) in cells and tissues is dangerous because it can result in energetic crises, cell death, and tissue dysfunction and promote pathological development (e.g., inflammatory conditions or stroke). Hypoxia can result from reduced environmental oxygen availability (e.g., lower environmental oxygen tension at high altitude), respiratory dysfunction (e.g., sleep apnea), circulatory dysfunction (e.g., myocardial infarction), oxygen transport deficiencies (e.g., anemia) or other pathological conditions (e.g., impaired geometry of oxygen diffusion in tumor environments) as well as from tissue hypoxia due to increased temporary oxygen demand (e.g., in skeletal muscle during exercise) (Figure 1).Figure 1: Types of hypoxia and hypoxia/hyperoxia responses.Here, we discuss whether severe hyperoxia might overwrite (protective) responses and adaptations to hypoxia. Created with Powerpoint (Microsoft Office LTSC Professional Plus 2021). O2: Oxygen.Maintaining an adequate oxygen supply is crucial. The negative outcomes of drops in oxygen availability can, in some cases, be efficiently mitigated by the use of hyperoxia. The administration of supplemental oxygen has become not only an essential clinical treatment in patients suffering from conditions involving hypoxia but also a preventive measure for patients at risk of becoming hypoxic, such as those undergoing surgery. It is also employed to reduce the strain of hypoxic environments (e.g., mountaineering at high altitudes). Oxygen supplementation is becoming increasingly popular as a potential means to increase athletic performance at low altitudes. Although the scientific interest in strategies to obtain performance or health benefits through the use of interventions involving hypoxia and/or hyperoxia is growing rapidly, the potential risks of such treatments are insufficiently understood. Based on recent findings from our own research and those of other groups, we aim to highlight caveats specifically linked to hyperoxia. Such considerations are crucial in a fast-evolving research field that is characterized by a wealth of established and emerging practical applications in clinics, sports and general health promotion. Clinical applications and risks of hyperoxia: Hypoxia in the blood (hypoxemia) can be readily reversed by supplemental oxygen administration, but whether this also preserves cellular and tissue functions is less clear. Although the World Health Organization recommends the use of supraphysiological oxygen tension (hyperoxia) during surgery to prevent surgical site infection and to ensure adequate oxygenation during the period when complications due to hypoxemia are most likely to occur, supraphysiological oxygen administration is associated with a higher risk of acute kidney, myocardial and lung injury, as well as with higher 30-day mortality scores, as reported in a landmark multicenter study.2 Increased mortality rates in critically ill patients receiving supplementary oxygen have specifically been reported after cardiac arrest, stroke, and traumatic brain injury or in patients with sepsis, the results of which have been summarized in a recent review.3 This observation is in contrast with long-established criteria for the treatment of surgical patients but is in agreement with basic research highlighting that even mild continuous hyperoxia (30% oxygen) can impair the delicate balance between the buildup of pro-oxidant factors (reactive oxygen species, reactive nitrogen species, and lipid peroxidation) and the resistance afforded by endogenous antioxidants in mice.4 Excess fuel of the respiratory chain and increased mitochondrial uncoupling are the primary factors involved in such an imbalance. Oxidative stress, oxidative modification and damage to all kinds of macromolecules, as well as cell death, tissue dysfunction and outcomes such as inflammation and vasoconstriction, are therefore potential consequences of hyperoxia.5 These effects may contribute to pathogenic events in various organs, primarily those of the respiratory, cardiovascular and central nervous systems. The lungs are particularly sensitive to hyperoxia, and pulmonary damage may lead to hypoxemia due to inadequate ventilation, which is an adverse outcome that has been known for many decades.6 Hyperoxia to increase performance: The effects of oxygen supplementation are driven by both the percentage of oxygen in inspired gas mixtures and their pressure. Thus, there is increasing interest in the use of supplemental oxygen at barometric pressures higher than 760 mmHg (i.e., hyperbaric oxygen [HBO]) to increase performance in athletes. HBO normally has a small effect on the amount of oxygen bound to hemoglobin but multiplies the amount of oxygen dissolved in the plasma, which is expected to lead to beneficial effects on physical performance or promote recovery. While repeated passive exposure to HBO may enhance performance via mechanisms such as improved mitochondrial respiration (maximal oxygen phosphorylation capacity and the highest rate at which mitochondria consume oxygen when the electron transport chain is uncoupled from adenosine triphosphate production) and increased mitochondrial mass, as indicated by increased MitoTracker Green (a mitochondrial mass marker) fluorescence (shown in muscle biopsies from middle-aged athletes),7 the effects of exercise training (2–3 weeks) during exposure to HBO are rather inconclusive and are discussed in more detail in a recent review.8 Importantly, the combination of two stressors, exercise and HBO, may increase the risk of maladaptive processes through processes such as excessive reactive oxygen species formation. Nevertheless, this remains speculative, and a better understanding of the complex mechanisms involved is needed. In addition, long exposure to HBO may even diminish hemoglobin levels (and therefore its oxygencarrying capacity) due to decreased erythropoietin stimulation, which in theory may reduce the amount of oxygen carried by blood under hyperoxic conditions. Normobaric oxygen supplementation is another strategy that may improve athletic performance, particularly in hypoxia. While short repeated 15-second bouts of oxygen supplementation (100%) prevented a decrease in arterial oxygen saturation and increased physical performance parameters when administered during hypoxic exercise,9 oxygen supplementation (100%) during recovery only (4 × 15 minutes) did not improve performance in hypoxia10 (both studies investigated human athletes). Rather, hyperoxic recovery periods appear to interfere with long-term alterations in the proteome following hypoxic exercise.10 This intriguingly indicates another risk of hyperoxia, namely, the blunting of potentially protective hypoxia responses. Unfortunately, the risks of hyperoxia are still not well defined, and the pronounced risks of severe hypoxia are frequently neglected. Regarding competitive sport settings, however, some clear regulations already exist. The International Olympic Committee, for example, prohibits national teams from bringing oxygen tanks and cylinders as well as hypoxic or hyperoxic tents or chambers into or around any Olympic Venue during the period of the Olympic Games, as was recently the case for the Summer Olympic Games in Paris in 2024.11 Maintaining oxygen homeostasis is key: Supraphysiological tissue oxygen levels have been found to occur in some animal models of mitochondrial diseases (e.g., a mouse model of Leigh syndrome), probably as a consequence of impaired oxygen utilization capacity due to mitochondrial deficiencies.12,13 Reducing environmental oxygen levels (to 11%) rescues many of the pathological features in these models.12,13 It therefore appears that both moderately increasing and decreasing oxygen availability can be beneficial, depending on the conditions. In contrast, any severe deviation from physiological oxygen homeostasis can be toxic.1 Accordingly, the use of supplemental oxygen in clinical settings needs to be appropriately dosed to avoid serious side effects.2,3 Subtoxic doses of hypoxia and hyperoxia induce physiological responses aimed at increasing the resilience of cells and tissues to subsequent more severe insults or adjusting oxygen homeostasis to new conditions (Figure 1). Altitude acclimatization or hypoxia conditioning effects (in which organisms, tissues or cells are exposed to moderate hypoxia to reduce susceptibility to hypoxic injuries in subsequent hypoxic conditions) are prominent examples of the possibility of harnessing these physiological effects to prevent high-altitude illnesses or to target other specific hypoxia-related diseases (such as stroke or myocardial infarction), respectively, as recently reviewed.5 Exercise under hypoxia (14.6% oxygen) during an exposure time of approximately 3 hours induces marked changes in blood protein abundance, leading to changes in proteomics patterns even days later.10 Notably, some of the molecular responses to hypoxia and hyperoxia surprisingly overlap; for example, both stimuli trigger protective effects against oxidative stress in mice.4 In contrast, some physiological responses are expectedly opposed, with hypoxia, for example, favoring systemic vasodilation, whereas hyperoxia is associated with systemic vasoconstriction. The mechanisms underlying the physiological and pathological responses to hypoxia, especially hyperoxia, and the interplay of hypoxic and hyperoxic responses remain poorly understood. Nevertheless, approaches such as intermittent hypoxia (usually 10–15% oxygen)-hyperoxia (often 30–34% oxygen) conditioning aim to take advantage of assumed complementary or synergistic outcomes.5 The physiological response to hypoxia is a crucial mechanism to protect cells and the whole organism from the potentially fatal risks of hypoxia. They involve delicate oxygen-sensing systems and intricate molecular and systemic response and adaptation mechanisms. At the cellular level, oxygen-dependent biochemical reactions, oxygen level-controlled regulation of specialized transcription factors (particularly hypoxia-inducible factors, which are counterintuitively also induced by hyperoxia) and the interrelated coordination of molecular signaling pathways mediate the sensing of decreased oxygen availability and molecular responses.5 These responses involve the upregulation of antioxidant systems, a switch to alternative, nonoxygen-dependent pathways of glucose (glycolysis) and fatty acid (reductive glutaminolysis) metabolism, and prosurvival signaling and rely on substantial transcriptomic and proteomic alterations.5 A network of peripheral and central oxygen sensors (largely operating on the basis of molecular oxygen sensors) is responsible for classical systemic responses, which include directly increased ventilation, pulmonary artery pressure, heart rate and cerebral blood flow, as well as gradual (after several hours to days) erythropoietin, hemoglobin and plasma volume responses. Together, these mechanisms ideally adapt cells (and organisms) to altered metabolic redox conditions and preserve adequate systemic oxygen delivery. In this way, hypoxia adaptations (but probably not adaptations to hyperoxia, although confirmatory research is needed) can partially remedy the performance decline in hypoxia by maintaining cellular functions and systemic oxygen availability. Importantly, these adaptations are also the foundation of protective effects against later hypoxic injuries. While maladaptation can occur (e.g., in the development of high-altitude illnesses), repeated exposure to hypoxia reduces this risk (acclimatization or conditioning). Implications for clinical and performance-related applications of hyperoxia: The finding that oxygen supplementation (100%) may prevent responses/ adaptations to hypoxic stimuli, at least at the proteomic level,10 adds important further caveats and potential mechanistic explanations to the increasingly recognized risks of oxygen supplementation in clinical conditions3 but also for performance improvement. While oxygen supplementation is undoubtedly clinically beneficial in many conditions associated with hypoxemia, it may also blunt the protective physiological responses to hypoxia and thereby contribute to potentially higher mortality rates in patient groups that have been summarized recently.3 In addition, hyperoxia may be detrimental in certain conditions in which mitochondrial oxygen utilization is impaired, such as in murine models of Leigh disease or in Friedreich ataxia.12,13 The individual determination of optimal oxygenation levels and the cessation of oxygen therapy when not acutely necessary, therefore, seem important considerations for future research and clinical practice. Appropriate personalization of hyperoxic treatments appears to be particularly relevant in high-altitude settings (e.g., in clinics at high altitudes or for oxygen supplementation administered during high-altitude sojourns—especially for training or competitions — to treat associated illnesses or improve performance), where they could be able to blunt high-altitude acclimatization. This may not be intended, especially if the patient or athlete plans to stay or return to high altitude again soon, potentially to compete. Clearly, in some cases of severe high-altitude illnesses (such as high-altitude edema in the brain or lungs), supplemental oxygen is indicated and can be life-saving. If oxygen supplementation can be avoided, such as for performance enhancement in noncompetitive sports under hypoxic conditions, the potential benefits should be carefully weighed against the risks. The possibility of hyperoxia blunting hypoxic adaptations also raises questions regarding intermittent hypoxia–hyperoxia conditioning. This method has recently been suggested to be superior to hypoxia conditioning by itself,5 but the molecular and functional/clinical outcomes have not been sufficiently investigated in appropriate (placebo-controlled) trials. In general, the dose of applied hyperoxia most likely determines its risk. While the moderate hyperoxia (often 30-34% oxygen, for a few minutes between several bouts of moderate hypoxia) used in intermittent hypoxia–hyperoxia conditioning likely does not interfere with hypoxia adaptations (although this remains to be experimentally confirmed), 80–100% oxygen – especially if administered repeatedly for more than 10–15 minutes or continuously for several hours or longer – probably does. Taken together, many unknowns remain regarding the physiological effects of hyperoxia, indicating important limitations for scientific considerations and practical applications. We believe that the following limitations deserve rapid clarification. First, and applying to all subsequent points, the optimal doses (most likely depending on individual predispositions) of hyperoxia applications remain to be elucidated. Second, the efficacy of hyperoxia for enhancing athletic performance under hypoxia, particularly normoxia, remains debated. Third, the appropriate and safe clinical oxygen supplementation approaches (including hyperoxia intensity, duration, and counterindications) remain to be better defined, especially when hyperoxia is used as a preventive measure. Fourth, the possibility that hyperoxia interferes with acclimatization/hypoxia adaptation processes needs to be addressed. Conclusion: Substantial alterations in oxygen availability (both reductions and increases) threaten physiological oxygen homeostasis. Cellular and systemic mechanisms are in place to preserve this homeostasis during deviations of normal oxygen levels, but they can fail. Hyperoxia can be employed to remedy adverse outcomes of hypoxia. However, the risks of oxygen supplementation are not fully understood and include potential tissue damage, increased mortality under certain conditions and possibly reduced acclimatization to hypoxic environments. A better understanding of the dose–response interactions of hyperoxia and hypoxia treatments is urgently needed. In addition to clinical applications, increasingly popular approaches for athletic and wellness purposes (for example, intermittent hypoxia–hyperoxia conditioning) require in-depth scientific assessment with regard to safety and efficacy.