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Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids

Cell Death & Differentiation volume 30, pages 2432–2445 (2023)Cite this article

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Abstract

Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.

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Fig. 1: Ionizing radiation increases intracellular ROS.
Fig. 2: Ionizing radiation induces ferroptosis.
Fig. 3: Ferroptosis and autophagy are reciprocally influenced by ionizing radiation.
Fig. 4: Mitophagy induced by ionizing radiation promotes ferroptosis.
Fig. 5: Free fatty acids released by mitophagy boost lipid peroxidation.
Fig. 6: Ionizing radiation boosts killing in mitophagy-activated tumors through ferroptosis in mice.
Fig. 7: Schematic of the proposed mechanism.

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All data generated and analyzed during the study are included in this article. Each experiment was performed at least three times independently.

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Funding

Funding

This work was supported by the National Nature Science Foundation of China (NO.11905264, HZ; NO.12175289, JW), the Hundred-Talent Program of the Chinese Academy of Sciences (NO.29Y763050, HZ), and the Science and Technology Research Project of Gansu Province (NO.22YF7WA024, HZ; NO.22JR5RA128, PY).

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Authors and Affiliations

  1. Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China

    Pengfei Yang, Jin Li, Tianyi Zhang, Qiuning Zhang, Ruifeng Liu, Junrui Hua, Jufang Wang & Heng Zhou

  2. School of Public Health, Yangzhou University, Yangzhou, China

    Pengfei Yang, Tianyi Zhang & Heng Zhou

  3. Renmin Hospital of Wuhan Economic and Technological Development Zone, Wuhan, China

    Jin Li

  4. Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China

    Yanxian Ren & Wen-An Wang

  5. Gansu Provincial Cancer Hospital, Gansu Provincial Academic Institute for Medical Sciences, Lanzhou, China

    Haining Li

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Contributions

HZ conceived and designed the experiment. PY, TZ, and YR performed the western blot and real-time PCR assays. PY and HL performed the flow cytometry assays. QZ performed the ELISA assays. PY, RL, and JH performed the immunofluorescence assays. TZ and YR performed the transmission electron microscopy assays. PY and JL performed the animal experiment. PY and RL performed the immunohistochemistry assays. JL, WW and TZ analyzed the data. HZ and PY wrote the original draft. JW modified and polished the manuscript.

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Correspondence to Jufang Wang or Heng Zhou.

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Yang, P., Li, J., Zhang, T. et al. Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids. Cell Death Differ 30, 2432–2445 (2023). https://doi.org/10.1038/s41418-023-01230-0

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