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

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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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No datasets were generated or analyzed during the current study.

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Funding

This study was supported by the National Natural Science Foundation of China (82170091, 82130001, 82272243, 81970069, and 82370048); National Key R&D Plan (2020YFC2003700); Shanghai Municipal Science and Technology Major Project (ZD2021CY001); Science and Technology Commission of Shanghai Municipality (20Z11901000, 20DZ2261200, 20XD1401200, and 22Y11900800); Clinical Research Plan of SHDC (SHDC2020CR5010-002); Shanghai Municipal Key Clinical Specialty (shslczdzk02201); Smart Healthcare Project of Zhongshan Hospital, Fudan University (project number 2020ZHZS18); Youth Science Project of Zhongshan Hospital, Fudan University (2023ZSQN21); and Shanghai Municipal Health Commission and Shanghai Municipal Administrator of Traditional Chinese Medicine (ZY(2021-2023)-0207-01).

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Author notes

  1. Xiaocen Wang, Tingting Wei, and Jinlong Luo contributed equally to this work.

Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China

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

  2. Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China

    Yuanlin Song

  3. Shanghai Respiratory Research Institute, Shanghai, China

    Yuanlin Song

  4. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China

    Yuanlin Song

  5. Department of Pulmonary Medicine, Qingpu Branch, Zhongshan Hospital, Fudan University, Shanghai, China

    Yuanlin Song

  6. Jinshan Hospital of Fudan University, Shanghai, China

    Yuanlin Song

Authors
  1. Xiaocen Wang
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  2. Tingting Wei
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  4. Ke Lang
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  9. Linlin Wang
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Contributions

Yuanlin Song, Dong Yang, and Linlin Wang contributed to the design of the study; Xiaocen Wang, Tingting Wei, and Jinlong Luo performed the in vivo experiment; Ke Lang, Zhaolin Gu, and Xinyi Ning performed the in vitro experiment; Xiaocen Wang, Tingting Wei, and Jinlong Luo performed the data analyses and wrote the manuscript; Yansha Song, Cuicui Chen, and Yencheng Chao helped perform the analysis with constructive discussions. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Linlin Wang, Dong Yang or Yuanlin Song.

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Wang, X., Wei, T., Luo, J. et al. Iron Overload–Dependent Ferroptosis Aggravates LPS-Induced Acute Lung Injury by Impairing Mitochondrial Function. Inflammation (2024). https://doi.org/10.1007/s10753-024-02022-5

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  • DOI: https://doi.org/10.1007/s10753-024-02022-5

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