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09-05-2024 | Acute Respiratory Distress-Syndrome | RESEARCH

Iron Overload–Dependent Ferroptosis Aggravates LPS-Induced Acute Lung Injury by Impairing Mitochondrial Function

Authors: Xiaocen Wang, Tingting Wei, Jinlong Luo, Ke Lang, Yansha Song, Xinyi Ning, Yencheng Chao, Zhaolin Gu, Linlin Wang, Cuicui Chen, Dong Yang, Yuanlin Song

Published in: Inflammation

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Abstract

Ferroptosis is a newly proposed form of programmed cell death that is iron-dependent and closely linked to oxidative stress. Its specific morphological changes include shrunken mitochondria, increased density of mitochondrial membrane, and rupture or disappearance of mitochondrial cristae. The main mechanism of ferroptosis involves excessive free iron reacting with membrane phospholipids, known as the Fenton reaction, resulting in lipid peroxidation. However, the role of iron in acute lung injury (ALI) remains largely unknown. In this study, LPS was instilled into the airway to induce ALI in mice. We observed a significant increase in iron concentration during ALI, accompanied by elevated levels of lipid peroxidation markers such as malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE). Treatment with the iron chelator deferoxamine (DFO) or ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed lipid peroxidation and significantly attenuates lung injury. Similarly, DFO or Fer-1 treatment improved the cell survival significantly in vitro. These results demonstrated that ferroptosis occurs during ALI and that targeting ferroptosis is an effective treatment strategy. Interestingly, we found that the increased iron was primarily concentrated in mitochondria and DFO treatment effectively restored normal mitochondria morphology. To further confirm the damaging effect of iron on mitochondria, we performed mitochondrial stress tests in vitro, which revealed that iron stimulation led to mitochondrial dysfunction, characterized by impaired basal respiratory capacity, ATP production capacity, and maximum respiratory capacity. MitoTEMPO, an antioxidant targeting mitochondria, exhibited superior efficacy in improving iron-induced mitochondrial dysfunction compared to the broad-spectrum antioxidant NAC. Treatment with MitoTEMPO more effectively alleviated ALI. In conclusion, ferroptosis contributes to the pathogenesis of ALI and aggravates ALI by impairing mitochondrial function.
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Metadata
Title
Iron Overload–Dependent Ferroptosis Aggravates LPS-Induced Acute Lung Injury by Impairing Mitochondrial Function
Authors
Xiaocen Wang
Tingting Wei
Jinlong Luo
Ke Lang
Yansha Song
Xinyi Ning
Yencheng Chao
Zhaolin Gu
Linlin Wang
Cuicui Chen
Dong Yang
Yuanlin Song
Publication date
09-05-2024
Publisher
Springer US
Published in
Inflammation
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-024-02022-5
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