2. Academic Validation
  3. Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes

Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes

  • J Mol Neurosci. 2025 Feb 17;75(1):23. doi: 10.1007/s12031-024-02302-7.
Gengxin Lu # 1 2 3,  Junyu Wu # 1 2 3,  Zhihui Zheng 1 2 3,  Zhezhi Deng 1 2 3,  Xue Xu 1 2 3,  Xintian Li 1 2 3,  Xiaoqiu Liang 1 2 3,  Weiwei Qi 1 2 3,  Shifeng Zhang 1 2 3,  Yuemin Qiu 1 2 3,  Minping Li 1 2 3,  Junjie Guo 4 5 6,  Haiwei Huang 7 8 9
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, China.
  • 2 Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, No.58 Zhongshan Road 2, Guangzhou, 510080, China.
  • 3 National Key Clinical Department and Key Discipline of Neurology, Zhongshan Road 2, Guangzhou, 510080, China.
  • 4 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, China. guojj57@mail.sysu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, No.58 Zhongshan Road 2, Guangzhou, 510080, China. guojj57@mail.sysu.edu.cn.
  • 6 National Key Clinical Department and Key Discipline of Neurology, Zhongshan Road 2, Guangzhou, 510080, China. guojj57@mail.sysu.edu.cn.
  • 7 Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, China. huanghw@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, No.58 Zhongshan Road 2, Guangzhou, 510080, China. huanghw@mail.sysu.edu.cn.
  • 9 National Key Clinical Department and Key Discipline of Neurology, Zhongshan Road 2, Guangzhou, 510080, China. huanghw@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39961873 DOI: 10.1007/s12031-024-02302-7
Abstract

Radiation brain injury (RBI) is a complication of cranial tumor radiotherapy that significantly impacts patients' quality of life. Astrocyte-secreted vascular endothelial growth factor (VEGF) disrupts the blood-brain barrier (BBB) in RBI. However, further studies are required to elucidate the complex molecular mechanisms involved. Reactive Oxygen Species (ROS) are closely linked to VEGF pathway regulation, with excessive ROS potentially disrupting this pathway. Mitochondria, the primary ROS-producing organelles, play a crucial role under irradiation. Our findings suggest that irradiation activates astrocytes with altered polarity, generating both cellular and mitochondrial ROS. Concurrently, mitochondrial morphology and function are disrupted, leading to defective Mitophagy and an accumulation of damaged mitochondria, which further exacerbates ROS damage. Urolithin A (UA) is a natural activator of Mitophagy. We found that UA promoted Mitophagy in irradiated astrocytes, reduced cellular and mitochondrial ROS, restored mitochondrial morphology and function, reversed VEGF overexpression, and attenuated the disruption of endothelial tight junction proteins in endothelial cells cultured with irradiated astrocyte supernatants. In conclusion, our study identifies a connection between impaired Mitophagy and VEGF overexpression in radiation-induced astrocytes. We also demonstrated UA may serve as a therapeutic strategy for protecting the tight junction protein in RBI by enhancing Mitophagy, reducing ROS accumulation, and downregulating VEGF expression.

Keywords

Astrocyte; Mitophagy; Radiation-induced brain injury; Urolithin A; VEGF.

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