2. Academic Validation
  3. MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury

MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury

  • Eur J Pharmacol. 2025 Oct 15:1005:178118. doi: 10.1016/j.ejphar.2025.178118.
Haibo Xie 1,  Jingyi Zhao 2,  Jian Chen 2,  Rui Li 2,  Hui Li 3,  Qifeng Wu 4,  Chen You 2,  Jiaxiang Zhang 5,  Bo Liang 6,  Qixing Zhu 7
Affiliations

Affiliations

  • 1 Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei, 230032, Anhui, China.
  • 2 Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
  • 3 Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen, Guangdong, China.
  • 4 Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, China.
  • 5 Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei, 230032, Anhui, China; Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China. Electronic address: zhangjiaxiang@ahmu.edu.cn.
  • 6 Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei, 230032, Anhui, China. Electronic address: anyiliangbo@vip.126.com.
  • 7 Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China; Institute of Dermatology, Anhui Medical University, Hefei, 230032, Anhui, China. Electronic address: zqxing@ahmu.edu.cn.
PMID: 40912515 DOI: 10.1016/j.ejphar.2025.178118
Abstract

Vascular endothelial cells (ECs) damage is closely related to kidney injury. Our previous research revealed the involvement of interferon regulatory factor 1 (IRF1)-mediated PANoptosis of renal ECs in trichloroethylene (TCE)-induced immune kidney injury. However, how IRF1 regulates ECs PANoptosis remains unclear. In this study, we explored the mechanism of PANoptosis in renal ECs by introducing TCE-sensitized mice model, in vitro experiments and population studies. We found that serum tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) were associated with kidney and ECs injury in patients with occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). The combination of TNF-α and IFN-γ influences the opening of the mitochondrial permeability transition pore (mPTP) in human umbilical vein endothelial cells (HUVECs), thereby promoting the release of mitochondrial Reactive Oxygen Species (mtROS) and mitochondrial DNA (mtDNA). The inhibition of mPTP opening through the application of cyclosporin A (CsA) led to a decrease in the cytoplasmic release of mtDNA and a subsequent reduction in cellular PANoptosis. CsA administration not only mitigated renal damage but also inhibited PANoptosis in renal ECs and suppressed the expression of IRF1 and Z-nucleic acid-binding protein 1 (ZBP1). IRF1 suppression alleviated cellular PANoptosis, whereas concurrent ZBP1 overexpression rescued it. In summary, TNF-α combined with IFN-γ induced mitochondrial mPTP opening and facilitated mtDNA release. The presence of mtDNA enhances the intranuclear transcription of IRF1, which in turn upregulates ZBP1 expression. ZBP1 recognizes mtDNA and contributes to cellular PANoptosis.

Keywords

Endothelial cell; Mitochondrial DNA; Mitochondrial permeability transition pore; PANoptosis; Trichloroethylene.

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