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Background <p>Traumatic brain injury (TBI) represents a critical form of acute brain injury, characterized by considerable mortality and morbidity. Recently, fibroblast growth factor 21 (FGF21), a multifaceted hormone predominantly synthesized in liver, has emerged as a promising neuroprotective agent. In the study, we aim to investigate whether FGF21 exerts protective effects against TBI and to further elucidate its underlying molecular mechanisms.</p> Methods <p>To elucidate the role of FGF21 in regulating SLC25A39-dependent mitochondrial GSH transport and providing protection against TBI-induced neurological deficits, a series of cellular and molecular techniques, including western blot analysis, real-time polymerase chain reaction, immunohistochemistry, transmission electron microscope, and behavioral assays, were employed.</p> Results <p>FGF21 knockout exacerbates neural apoptosis and brain edema, increases lesion volume, and worsens neurological deficits following TBI. Remarkably, these pathological alterations were substantially mitigated with subsequent administration of recombinant FGF21. Importantly, FGF21 was found to prevent mitochondrial damage and sustain redox homeostasis post-TBI. Mechanistically, we observed that FGF21 enhances the mitochondrial uptake of glutathione (GSH), an essential redox metabolite, by targeting SLC25A39, a recently identified mitochondrial GSH transporter. FGF21 does not influence the transcriptional production of SLC25A39 but enhances its protein expression by inhibiting degradation via the mitochondrial protease AFG3L2. Furthermore, in neuron-specific Slc25a39 knockout mice, FGF21 was unable to exert its neuroprotective effects.</p> Conclusion <p>Our findings provide preliminary evidence that FGF21 confers protective effects against mitochondrial oxidative stress-related damage following TBI. Additionally, we elucidated a novel role for SLC25A39-dependent mitochondrial GSH transport in both the pathological processes subsequent to TBI and the physiological functions of FGF21.</p>

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FGF21 maintains redox homeostasis and promotes neuronal survival after traumatic brain injury by targeting SLC25A39-mediated mitochondrial GSH transport

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月2日

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  • Lekai Wang,
  • Weiwei Li,
  • Xun Wu,
  • Qing Ouyang,
  • Bing Sun,
  • Jianing Luo,
  • Heng Guo,
  • Tao Yang,
  • Yuan Ma

摘要

Background

Traumatic brain injury (TBI) represents a critical form of acute brain injury, characterized by considerable mortality and morbidity. Recently, fibroblast growth factor 21 (FGF21), a multifaceted hormone predominantly synthesized in liver, has emerged as a promising neuroprotective agent. In the study, we aim to investigate whether FGF21 exerts protective effects against TBI and to further elucidate its underlying molecular mechanisms.

Methods

To elucidate the role of FGF21 in regulating SLC25A39-dependent mitochondrial GSH transport and providing protection against TBI-induced neurological deficits, a series of cellular and molecular techniques, including western blot analysis, real-time polymerase chain reaction, immunohistochemistry, transmission electron microscope, and behavioral assays, were employed.

Results

FGF21 knockout exacerbates neural apoptosis and brain edema, increases lesion volume, and worsens neurological deficits following TBI. Remarkably, these pathological alterations were substantially mitigated with subsequent administration of recombinant FGF21. Importantly, FGF21 was found to prevent mitochondrial damage and sustain redox homeostasis post-TBI. Mechanistically, we observed that FGF21 enhances the mitochondrial uptake of glutathione (GSH), an essential redox metabolite, by targeting SLC25A39, a recently identified mitochondrial GSH transporter. FGF21 does not influence the transcriptional production of SLC25A39 but enhances its protein expression by inhibiting degradation via the mitochondrial protease AFG3L2. Furthermore, in neuron-specific Slc25a39 knockout mice, FGF21 was unable to exert its neuroprotective effects.

Conclusion

Our findings provide preliminary evidence that FGF21 confers protective effects against mitochondrial oxidative stress-related damage following TBI. Additionally, we elucidated a novel role for SLC25A39-dependent mitochondrial GSH transport in both the pathological processes subsequent to TBI and the physiological functions of FGF21.