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Updated: Aug 7, 2025
Expression and Purification of Nuclease-Free Oxygen Scavenger Protocatechuate 3,4-Dioxygenase
Published on: November 8, 2019
Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes
Alan H Baik1, Augustinus G Haribowo2, Xuewen Chen3
1Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
Abstract:
Oxygen is toxic across all three domains of life. Yet, the underlying molecular mechanisms remain largely unknown. Here, we systematically investigate the major cellular pathways affected by excess molecular oxygen. We find that hyperoxia destabilizes a specific subset of Fe-S cluster (ISC)-containing proteins, resulting in impaired diphthamide synthesis, purine metabolism, nucleotide excision repair, and electron transport chain (ETC) function. Our findings translate to primary human lung cells and a mouse model of pulmonary oxygen toxicity. We demonstrate that the ETC is the most vulnerable to damage, resulting in decreased mitochondrial oxygen consumption. This leads to further tissue hyperoxia and cyclic damage of the additional ISC-containing pathways. In support of this model, primary ETC dysfunction in the Ndufs4 KO mouse model causes lung tissue hyperoxia and dramatically increases sensitivity to hyperoxia-mediated ISC damage. This work has important implications for hyperoxia pathologies, including bronchopulmonary dysplasia, ischemia-reperfusion injury, aging, and mitochondrial disorders.
Insights
Excess oxygen (hyperoxia) damages key cellular proteins containing iron-sulfur clusters (ISC), impairing vital functions like energy production. This damage creates a cycle of toxicity, impacting lung health and other conditions.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- Oxygen is essential for life but toxic at high concentrations (hyperoxia).
- The molecular mechanisms underlying oxygen toxicity are not fully understood.
- Iron-sulfur cluster (ISC) proteins are crucial for many cellular processes.
Purpose of the Study:
- To systematically investigate cellular pathways affected by hyperoxia.
- To identify the specific molecular targets of oxygen toxicity.
- To elucidate the role of ISC proteins in hyperoxia-induced damage.
Main Methods:
- Systematic investigation of cellular pathways.
- Analysis of protein stability in hyperoxia.
- Use of primary human lung cells and a mouse model (Ndufs4 KO).
- Assessment of mitochondrial oxygen consumption and electron transport chain (ETC) function.
Main Results:
- Hyperoxia destabilizes specific ISC-containing proteins.
- Impaired functions include diphthamide synthesis, purine metabolism, nucleotide excision repair, and ETC function.
- The ETC is highly vulnerable, leading to decreased mitochondrial oxygen consumption and a cycle of damage.
- ETC dysfunction exacerbates hyperoxia sensitivity and ISC damage.
Conclusions:
- Hyperoxia induces cellular damage by destabilizing ISC proteins, particularly affecting the ETC.
- A feedback loop of mitochondrial dysfunction and tissue hyperoxia contributes to toxicity.
- Findings have implications for understanding and treating hyperoxia-related pathologies.
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