MassIVE MSV000091206

Partial Public PXD039867

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

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Description

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. [doi:10.25345/C5GH9BK44] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: lung ; hyperoxia ; iron-sulfur cluster

Contact

Principal Investigators:
(in alphabetical order) 		Isha Jain, Gladstone Institutes, USA
Submitting User: kxchen

Publications

Baik AH, Haribowo AG, Chen X, Queliconi BB, Barrios AM, Garg A, Maishan M, Campos AR, Matthay MA, Jain IH.
Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes.
Mol Cell. 2023 Mar 6;S1097-2765(23)00116-8. doi: 10.1016/j.molcel.2023.02.013.

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