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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.

SUBMITTER: Baik AH

PROVIDER: S-EPMC10148707 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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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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Project description:Fe-organic matter (Fe-OM) complexes are abundant in the environment and, due to their mobility, reactivity, and bioavailability, play a significant role in the biogeochemical Fe cycle. In photic zones of aquatic environments, Fe-OM complexes can potentially be reduced and oxidized, and thus cycled, by light-dependent processes, including abiotic photoreduction of Fe(III)-OM complexes and microbial oxidation of Fe(II)-OM complexes, by anoxygenic phototrophic bacteria. This could lead to a cryptic iron cycle in which continuous oxidation and rereduction of Fe could result in a low and steady-state Fe(II) concentration despite rapid Fe turnover. However, the coupling of these processes has never been demonstrated experimentally. In this study, we grew a model anoxygenic phototrophic Fe(II) oxidizer, Rhodobacter ferrooxidans SW2, with either citrate, Fe(II)-citrate, or Fe(III)-citrate. We found that strain SW2 was capable of reoxidizing Fe(II)-citrate produced by photochemical reduction of Fe(III)-citrate, which kept the dissolved Fe(II)-citrate concentration at low (<10 μM) and stable concentrations, with a concomitant increase in cell numbers. Cell suspension incubations with strain SW2 showed that it can also oxidize Fe(II)-EDTA, Fe(II)-humic acid, and Fe(II)-fulvic acid complexes. This work demonstrates the potential for active cryptic Fe cycling in the photic zone of anoxic aquatic environments, despite low measurable Fe(II) concentrations which are controlled by the rate of microbial Fe(II) oxidation and the identity of the Fe-OM complexes.IMPORTANCE Iron cycling, including reduction of Fe(III) and oxidation of Fe(II), involves the formation, transformation, and dissolution of minerals and dissolved iron-organic matter compounds. It has been shown previously that Fe can be cycled so rapidly that no measurable changes in Fe(II) and Fe(III) concentrations occur, leading to a so-called cryptic cycle. Cryptic Fe cycles have been shown to be driven either abiotically by a combination of photochemical reduction of Fe(III)-OM complexes and reoxidation of Fe(II) by O2, or microbially by a combination of Fe(III)-reducing and Fe(II)-oxidizing bacteria. Our study demonstrates a new type of light-driven cryptic Fe cycle that is relevant for the photic zone of aquatic habitats involving abiotic photochemical reduction of Fe(III)-OM complexes and microbial phototrophic Fe(II) oxidation. This new type of cryptic Fe cycle has important implications for biogeochemical cycling of iron, carbon, nutrients, and heavy metals and can also influence the composition and activity of microbial communities.

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

Publications

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

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