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WHEN OXYGEN IS TOXIC

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Why Too Much Oxygen Can Be Deadly: The Hidden Molecular Consequences of Hyperoxia

by Nic Rolph, PA-S

Oxygen keeps us alive—but in excess, it can quietly unravel critical cellular functions. A groundbreaking study by Baik et al. (2023) in Molecular Cell shines a light on why hyperoxia (too much oxygen) is toxic, and reveals a hidden mechanism behind its damaging effects.

The Mystery of Oxygen Toxicity

We’ve long known that both oxygen deprivation (hypoxia) and oxygen overload (hyperoxia) are harmful. While hypoxia research has led to major discoveries like the Nobel Prize-winning work on HIF (Hypoxia-Inducible Factors), hyperoxia has remained less understood—until now.

Baik and colleagues tackled a fundamental biological question: Why is oxygen toxic at the molecular level?

The Culprit: Fragile Iron-Sulfur Proteins

Using a combination of genome-wide CRISPR screening, proteomics, and in vivo experiments, the researchers identified a specific class of proteins highly vulnerable to excess oxygen: iron-sulfur cluster (Fe-S)-containing proteins.

These clusters act like tiny biochemical power stations inside proteins, but they’re extremely sensitive to oxidation. Under hyperoxic conditions, certain Fe-S proteins degrade, compromising several key cellular pathways:

  • Diphthamide synthesis – crucial for accurate protein translation.
  • De novo purine biosynthesis – needed for DNA and RNA building blocks.
  • Nucleotide excision repair (NER) – repairs damaged DNA.
  • Mitochondrial electron transport chain (ETC) – essential for energy production.

A Vicious Cycle of Oxygen Damage

Perhaps the most striking discovery was the feedback loop of cellular damage:

  1. Hyperoxia damages the ETC, lowering oxygen consumption;
  2. this increases local tissue oxygen levels even more,
  3. which leads to more damage—a self-amplifying loop Baik et al. called “cyclic oxygen toxicity.”

This cycle can explain why supplemental oxygen—while lifesaving—is also associated with complications in neonatal care, ICU patients, and chronic diseases.

From Petri Dishes to Lungs

The team validated their findings in human cells, mice, and even primary lung tissue. In a mouse model of hyperoxic lung injury, the same Fe-S proteins degraded rapidly—especially those in the ETC. Mice with preexisting ETC defects (like the Ndufs4 KO model) showed extreme sensitivity, confirming the ETC as the “weakest link” in the oxygen toxicity chain.

Bigger Picture: Aging, Disease, and Therapy

This study suggests that hyperoxia might contribute to a wide range of diseases—from premature infant lung injury and ischemia-reperfusion damage to neurodegenerative and mitochondrial disorders. It also offers a potential explanation for why antioxidant therapies have largely failed: superoxide isn’t the only villain—molecular oxygen itself may be enough to destabilize these proteins.

Rethinking Oxygen Therapy

Given these findings, clinicians may need to rethink how we use oxygen in medical settings. Rather than focusing solely on delivering “more oxygen,” we might need to tailor therapy to a patient’s oxygen-processing capacity—especially in those with mitochondrial or genetic vulnerabilities.

What’s Next?

Future research may explore:

  • Therapeutic hypoxia to interrupt the damage cycle.
  • Genetic screening to identify patients vulnerable to oxygen toxicity.
  • New drugs to stabilize Fe-S proteins in oxidative environments.

Takeaway

Oxygen is life-sustaining—but Baik et al. reveal it’s also a molecular saboteur under the wrong conditions. This landmark study not only explains the elusive biology of oxygen toxicity but opens new doors for safer therapies and deeper understanding of metabolic diseases.

Note from Dr. Christine Ebert-Santos, MD, MPS of Ebert Family Clinic in the Colorado Rocky Mountains at 9000’/2743m: newborns, children with respiratory infections or high altitude pulmonary edema, and people with sleep apnea are advised to use oxygen at high altitude. The level of oxygen saturation achieved with this treatment is well below normal sea-level values, so unlikely to cause any negative effects.

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KYRGYZSTAN VS SUMMIT COUNTY, COLORADO: EXERCISE AT ALTITUDE

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How does the low oxygen environment at altitude affect our ability to exercise?  What is the risk for developing harmful changes in the heart and lungs? Does sleep apnea contribute to these risks? Can supplemental oxygen reverse or reduce these risks and increase our exercise ability at altitude?

An audience of conference participants sit observing a slide in a presentation reading "Cardiac function and PH in 97 Kyrgyz Highlander and 76 Lowlander (50% women).

These important questions have been studied by an international research team conducting tests on residents of the Tien Shan mountain range in Kyrgyzstan, 2500-3500 m (8,200 to 11,482 feet). Dr. Silvia Ulrich presented some of their findings at the Hypoxia 2025 conference in Lake Louise in the Canadian Rocky Mountains this past winter. Using an exercise bike they measured ECG, pulmonary gas exchange and oxygen saturation in healthy highlanders. Participants’ average age was 48 years, 46 % were women, and their average oxygen saturation (SpO2) at rest was 88%. Normal occupations include nomadic herdsmen, hunters and soldiers who usually travel by car or horse, with no prior experience cycling or running. An echocardiogram was performed to assess pulmonary artery pressures (PAP) and right heart function.

Arterial blood gas analysis at baseline showed a normal pH, low oxygen, mildly decreased carbon dioxide and bicarbonate, and higher hemoglobin concentrations. Bicarbonate values were 22-26 moles/L. In Summit county, in the Rocky Mountains of Colorado, with residents living between 2500 to 3300 m bicarbonate values are 17-20 moles/L.

Results showed their peak oxygen uptake, and peak work rate was reduced by one quarter compared to predicted values for lowlanders. Oxygen saturation decreased during exercise. “Exercise limitation was related to an exercise -induced worsening of hypoxemia, high ventilation equivalents for oxygen uptake and carbon dioxide output, a reduced external work efficiency and a lower peak heart rate than predicted for age.” (1) In other words, they had to breathe harder to maintain their oxygen and carbon dioxide at normal values and use more effort for the same musculoskeletal output. Their heart rate did not increase as much as a person from lower altitude doing the same work.

There is little research on exercise capacity in long-term residents at altitude.  Most studies focus on athletes or comparing healthy acclimatized men to recent arrivals. The hypoxic environment is a known risk for pulmonary hypertension, which can lead to exercise intolerance and fatigue that is reversible with descent or oxygen use when diagnosed in a timely manner. Sleep apnea with the accompanying hypoxic episodes adds to this risk. Summit County residents show improvement in both systemic and pulmonary hypertension with supplemental oxygen during sleep, according to local health care providers.

Kyrgyzstan residents studied showed a strong correlation between  the incidence of sleep apnea with hypoxia (time below 90% SpO2), and abnormal pulmonary artery pressures. Echocardiograms compared 97 highlanders with 76 lowlanders who were asymptomatic. Between 6% and 35% had increased PAP depending on which definition is used. 

A slide at a conference presentation on the effect of high-dose SOT on pulmonary artery pressures and cardiac output in highlanders at risk for PH at 3250 meters.

The research team also evaluated their response to supplemental oxygen at altitude and 760m elevation using the six minute walk test. Although the test subjects reported less shortness of breath and had higher measured oxygen levels they were not able to walk further. Supplemental oxygen did reduce pulmonary artery pressures in those at risk when tested at 3,200 m.

A slide from a presentation on an experiment where oxygen levels in residents of high altitude in Kyrgyzstan are measured during a 6-minute walk.

This research was conducted by a crew of scientists who brought all the equipment with them to a basic medical clinic in a village.

Summit County cardiologist Warren Johnson was impressed by the numbers of people with elevated pressures in their lungs. “It could be as high as 30 per cent of adults,” he told local physicians. Symptoms are subtle: decreased exercise tolerance, mild shortness of breath, trouble sleeping, high red blood cell counts. Most people just think they are out of condition or aging.

A study in Spiti Valley India of residents living at 9000-13000 ft found an incidence of three per cent with PH.  Dr Johnson suspects this is a highly adapted population with centuries of mountain living.

Diagnosing this condition early with Echocardiogram can prevent serious disability.  Treatment is as simple as sleeping on oxygen. These measurements and much more are performed on a daily basis at the St. Anthony Summit Hospital, a 34-bed hospital serving five counties in Colorado, located at 2800 m. A parallel study to establish baseline normal values for the healthy population and identify the risk for pulmonary hypertension in asymptomatic mountain residents would be valuable for health care providers who are frequently asked to counsel residents on the risk of living at altitude.

References

Forrer A, Scheiwiller PM, Mademilov M, Lichtblau M, Sheraliev U, Marazhapov NH, Saxer S, Bader P, Appenzeller P, Aydaralieva S, Muratbekova A, Sooronbaev TM, Ulrich S, Bloch KE, Furian M. Exercise Performance in Central Asian Highlanders: A Cross-Sectional Study. High Alt Med Biol. 2021 Dec;22(4):386-394. doi: 10.1089/ham.2020.0211. Epub 2021 Aug 24. PMID: 34432548.

Lichtblau M, Saxer S, Furian M, Mayer L, Bader PR, Scheiwiller PM, Mademilov M, Sheraliev U, Tanner FC, Sooronbaev TM, Bloch KE, Ulrich S. Cardiac function and pulmonary hypertension in Central Asian highlanders at 3250 m. Eur Respir J. 2020 Aug 20;56(2):1902474. doi: 10.1183/13993003.02474-2019. PMID: 32430419.

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Sharing at the Chateau: 23rd International Hypoxia Symposium in Lake Louise

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I attended the 23rd International Hypoxia Symposium in Lake Louise, Canada to present some of the research on altitude I’ve been conducting in Colorado. The conference has been going on since 1979, and for the past 26  years the organizers have been Robert Roach and Peter Hackett, world-renowned medical researchers from Colorado. Meeting most of the famous altitude researchers from all over the world was an inspiration.  Personal talks and sharing information were equally important to imbibing the latest knowledge about hypoxia and hemoglobin.

A slide is projected onto a screen over the heads of conference participant, depicting statistics showing infant birthweight in mammals decreasing over increasing elevations.
From Jay Storz’s presentation at the 2025 International Hypoxia Symposia in Lake Louise, Canada

Antarctic Icefish: Life Without Hemoglobin, was presented by Kristen O’Brien, expanding the concept of oxygen distribution in living beings and introducing us to varieties of fish we have never heard of. Her talk was followed by our “Mice and Men” guy, Jay Storz (and colleague Graham Scott), who along with Jon Velotta mentioned in our blogpost on the show “This Podcast Will Kill You” collect the large eared deer mice from peaks such as Blue Sky Mountain to study adaptation to hypoxia in their labs. The talk recognized for first prize was on Altitude Headaches, including a discussion of migraines, by Andrew Charles.

Every evening there was a banquet and speaker.  Astronaut Jessica Meir spent 210 days aboard the space station.  She shared a wide range of challenges such as exercising without gravity, choosing a compatible crew, getting boxes of treats from home, and effects of prolonged weightlessness on your eyes and muscles.

A slide projected onto a conference room screen before participants depicts results for six minute walks on and off oxygen.
Silvia Ulrich presented on Pulmonary Circulation of Central Asian Highlanders at the 2025 International Hypoxia Symposium at Lake Louise, Canada.

The research I would like to see duplicated in Summit County was from Kyrgyzstan, where Silvia Ulrich studied the hearts and lungs of the permanent residents at 9000 feet using the six minute walk as one of her tools.  They did not score higher when studied at sea level! She ran tests for pulmonary hypertension, which could be important here.

Of course, there was a talk on Sleep Disordered Breathing (sleep apnea) by Esther Schwarz, something we pay a great deal of attention to in our own clinic in Frisco, Colorado and have several research projects on the improvement we see with supplemental oxygen. The role of mitochondria in cellular function in hypoxia was presented by Dr. Christian Arias-Reyes, a researcher at Seattle Children’s Hospital who is originally from La Páz, Bolivia.  I met him at the Chronic Hypoxia conference in 2019 when he was a graduate student in Quebec and again in La Páz at this year’s conference. 

A line of people pose in front of a cafe with signs and plants hanging above a stone-tiled street lined with buildings
Altitude experts Dr. Zubieta Calleja, Dr. Christian Arias-Reyes, Dr. Michele Samaja and Dr. Christine Ebert-Santos with colleagues of the Hypoxia Symposia in front of a pizzeria in Coroico, Bolivia.

A deep dive into how our neurons react to hypoxia in the brain by releasing nitric oxide to dilate blood vessels and preserve circulation reenforced the counseling I do here in my clinic to parents whose children have breath holding spells or babies with dips in their oxygen on home monitors. Along with all the millions of children and adults living at 12,000 feet in Bolivia, we can witness that hypoxia does not cause brain damage. (Not to be confused with anoxia, a complete lack of oxygen.)

Lastly, Nobel prize winner and fellow pediatrician Gregg Semenza spoke on research to find a blocking compound against HIF- hypoxia inducible factor, as a cure for some cancers. Gregg’s work was described in our blog on the Nobel prize being awarded to scientists working on hypoxia. HIF deserves its own blogpost! More about cancer and hypoxia at altitude from the Chronic Hypoxia Conference in La Páz.

I was selected to give my presentation, “Colorado Kids Are Smaller” to both conferences. I have been working on this for 20 years. You can read more on our blog where it is titled “Mountain Kids Are Smaller”.  My goal is to get a unique growth chart for children under age two at altitude, to save parents and providers anxiety and money trying to get our kids to “be the same” as those at sea level.

The most useful tidbit of information came on the bus ride back to Calgary. Dr Heimo Mairbaurl, PhD shared that a quarter dose of acetazolamide was sufficient for his acute mountain sickness symptom prevention, 62 mg for a guy over 6 feet tall. Although there was a study on a new possible preventive treatment, prochlorperazine, done on Mount Blue Sky last fall, I still swear by the old drug formerly known as “Diamox”.