Unraveling Oxygen's Impact on Protein Dynamics

Understanding the adverse effects of insufficient oxygen becomes apparent with the simple act of holding ones breath for too long.

However, the question arises: can one also experience negative consequences from an excess of oxygen? Undoubtedly, inhaling air with an elevated oxygen concentration beyond the body's requirements can lead to health issues, and in severe cases, even death.

Despite a limited amount of research on this subject, scientists have possessed little knowledge about how the body detects an excess of oxygen. A recent study conducted by Gladstone Institutes has significantly expanded the scientific understanding of the underlying mechanisms and their implications for health.

The study's findings, published in the journal Science Advances, elucidate the impact of breathing air with varying oxygen levels—ranging from insufficient to optimal and excessive—on the synthesis and breakdown of various proteins in the lungs, heart, and brain of mice.

Notably, the research sheds light on a specific protein that appears to play a central role in regulating cellular responses to hyperoxia.

“These results have implications for many different diseases. More than 1 million people in the US breathe supplemental oxygen every day for medical reasons, and studies suggest it could be making things worse in some cases. That’s just one setting where our work is starting to explain what’s happening and how the body responds,” says Gladstone Assistant Investigator Isha Jain, PhD, senior author of the new study.

Understanding Oxygen’s Effects

The majority of previous studies on oxygen levels have primarily delved into the molecular consequences of insufficient oxygen. Even within this domain, the predominant emphasis has been on understanding the impact of low oxygen levels on the activation or deactivation of specific genes.

Our study enters uncharted territory by using mice and looking downstream of gene expression at which proteins abnormally accumulate or degrade in response to different oxygen concentrations.”

Kirsten Xuewen Chen, Study First Author and Graduate Student, University of California- San Francisco.

This study builds upon the team’s previous research, which uncovered that excessive oxygen triggers the degradation of specific proteins containing iron and sulfur clusters. This degradation ultimately results in cellular dysfunction.

Now, we wanted to get a more dynamic picture of how proteins are regulated when oxygen levels are too high or too low.”

Kirsten Xuewen Chen, Study First Author and Graduate Student, University of California- San Francisco.

To achieve this, the researchers subjected mice to varying oxygen levels—8%, 21% (representative of Earth’s usual atmospheric composition), and 60%—over the course of several weeks.

Concurrently, the mice were provided with food containing a specific form of nitrogen, which their bodies integrated into newly synthesized proteins. This nitrogen isotope served as a “label,” allowing the researchers to determine the turnover rates—the equilibrium between protein synthesis and degradation—for numerous proteins in the lungs, heart, and brain.

Jain states, “We’re grateful to our collaborators who are the experts in this technique, known as stable isotope labeling of amino acids in mice. Without it, we could not have done this study.”

A Key Protein Builds Up

The scientists observed that oxygen levels had a more pronounced impact on proteins in the lungs of mice compared to those in the heart or brain.

They pinpointed specific proteins exhibiting abnormal turnover rates in response to either high or low oxygen levels. Of particular interest was a protein called MYBBP1A, which accumulated in high-oxygen conditions. MYBBP1A serves as a transcription regulator, directly influencing gene expression.

This caught our eye because prior research has shown that other transcription factors called hypoxia-inducible factors, or HIFs, play a big role in cells’ response to low oxygen. Our work nominates MYBBP1A for a related role in hyperoxia signaling.”

Kirsten Xuewen Chen, Study First Author and Graduate Student, University of California- San Francisco.

MYBBP1A plays a role in the synthesis of ribosomes, the cellular "machines" responsible for constructing proteins. Additional experiments provided indications that, in the presence of elevated oxygen levels, the accumulation of this protein in the lungs might influence the production of ribosomal RNA, a critical component of ribosomes.

Currently, Jain's team is delving into the precise molecular role of MYBBP1A during hyperoxia, investigating whether its response is protective or detrimental.

This research holds the potential to pave the way for innovative treatments targeting the MYBBP1A protein or related molecules, with the aim of mitigating the adverse effects of hyperoxia—similar to the extensive research efforts directed at HIF proteins in low-oxygen conditions.

First-of-Its-Kind Dataset

This groundbreaking study introduces an unprecedented dataset detailing protein turnover rates in various tissues of mice exposed to varying oxygen levels.

The team anticipates that these findings will serve as a catalyst, inspiring other researchers to delve deeper into the repercussions of excessive or insufficient oxygen on the body. Such investigations have the potential to revolutionize disease treatment approaches.