Dataset Information

Oxygen Toxicity Causes Cyclic Damage by Destabilizing Specific Fe-S Cluster-Containing Protein Complexes

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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Isha Jain

PROVIDER: MSV000091206 | MassIVE | Sun Feb 05 10:25:00 GMT 2023

SECONDARY ACCESSION(S): PXD039867

REPOSITORIES: MassIVE

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Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes.

Baik Alan H AH Haribowo Augustinus G AG Chen Xuewen X Queliconi Bruno B BB Barrios Alec M AM Garg Ankur A Maishan Mazharul M Campos Alexandre R AR Matthay Michael A MA Jain Isha H IH

Molecular cell 20230308 6

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 ...[more]

PMID: 36893757

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