The latest research reveals the key way that excess oxygen damages health

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The latest research reveals the key way that excess oxygen damages health

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Cell Sub-Journal: The latest research reveals the key way that excess oxygen damages health

When it comes to oxygen, we often think about the benefits of oxygen, and the dangers of lack of it. But breathing air with a higher oxygen content (21 percent) than is typical in Earth’s atmosphere can cause organ damage, seizures, and even death in humans and animals, especially if it exceeds the body’s oxygen needs.

For example, recent research suggests that breathing too much supplemental oxygen may be harmful for heart patients and premature babies. Likewise, in obstructive sleep apnea, the sudden increase in oxygen following the pause has been shown to be a key reason for how the disease increases patients’ risk of chronic health problems.

Nonetheless, the mechanisms of these effects remain obscure. Many researchers believe that reactive oxygen species—metabolites or derivatives of oxygen with higher reactivity—may play a role in hyperoxic conditions, damaging our genome and many molecules in our cells, but there is little evidence that excess How oxygen affects specific enzymes and pathways.

Recently, the research team of the Gladstone Institutes published a research paper entitled: Oxygen Toxicity Causes Cyclic Damage by Destabilizing Specific Fe-S Cluster-Containing Protein Complexes in the journal Molecular Cell

The study uncovered how excess oxygen alters a handful of proteins in our cells that contain iron and sulfur — a chemical process similar to how iron rusts. In turn, these “rusty” proteins trigger a cascade of events that damage cells and tissues, with implications for diseases such as heart attacks and sleep apnea.

An understudied problem

High concentrations of oxygen are toxic to any form of life, from bacteria and plants to animals and humans. Of course, lack of oxygen can also be fatal.

There is a middle value of no more and no less, an amount at which most life on Earth can thrive.

While clinicians have long studied how a lack of oxygen affects cells and tissues (such as in heart attacks and strokes) , the effects of excess oxygen are relatively understudied.

“For many years, in treating patients with conditions like heart attacks, more oxygen was better, or at least benign, in a way,” says Alan Baik , MD, a postdoctoral scholar in Jain’s lab and co-author of the study. Cardiologist at the University of California, San Francisco (UCSF) .  “But now there is a growing body of clinical research showing that excess oxygen can actually lead to worse outcomes. This prompts our need to better understand why excess oxygen is toxic .”

Find out with CRISPR

To address this issue, Isha H. Jain ‘s research team turned to the genome editing technology CRISPR to test the role of various genes in hyperoxia.

Using CRISPR technology, the researchers knocked out more than 20,000 different genes from human cells grown in the lab, then compared how each group of cells grew under 21 percent oxygen versus 50 percent oxygen.

“This unbiased screen allowed us to explore the contribution of thousands of different molecular pathways under hyperoxic conditions, rather than just focusing on pathways we already suspected might be involved,” said Isha H. Jain . identified molecules that had never before been linked to oxygen toxicity.”

In the screen, four molecular pathways stood out, shown to be involved in the effects of hyperoxia. They are involved in a variety of cellular functions, including repairing damaged DNA, generating new DNA building blocks, and generating cellular energy.

Common protein cluster

At first, the research team could not determine what these four molecular pathways had in common, and why they were all affected by high oxygen levels.

After some research, it was discovered that each pathway possesses a key protein that contains iron atoms linked to sulfur atoms in its molecular structure, so-called “iron-sulfur clusters” (Fe-S clusters) .

They found that hyperoxia disrupted Fe-S-containing cluster proteins, resulting in impaired diacetamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function .

Hyperoxia induces acute lung injury in a mouse model. And in primary human lung cells and a mouse lung oxygen toxicity model, hyperoxia led to the degradation of specific ISC-containing proteins in both mouse and human lung cells .

They further demonstrated that ETCs are most susceptible to damage by hyperoxia, resulting in reduced mitochondrial oxygen consumption, which leads to further tissue hyperoxia and impairment of the ISC pathway .

Subsequently, the researchers also demonstrated in the Ndufs4 KO mouse model that primary ETC dysfunction also leads to hyperoxia in lung tissue and significantly increases sensitivity to hyperoxia-mediated ISC injury .

“An important takeaway is that hyperoxia does not affect cells and tissues solely through reactive oxygen species , as many have assumed,” Jain said. “This means that the use of antioxidants to combat reactive oxygen species to some extent is unlikely to be sufficient to prevent oxygen toxicity.”

This work has important implications for hyperoxic pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and therapeutic guidance for mitochondrial disease.

Paper link :
https://doi.org/10.1016/j.molcel.2023.02.013

The latest research reveals the key way that excess oxygen damages health

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