HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons

作者全名：Li, Xiaolan; Ran, Qin; He, Xiang; Peng, Dan; Xiong, Anying; Jiang, Manling; Zhang, Lei; Wang, Junyi; Bai, Lingling; Liu, Shengbin; Li, Shiyue; Sun, Baoqing; Li, Guoping

作者地址：[Li, Xiaolan; He, Xiang; Sun, Baoqing] Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis, Dept Clin Lab,Natl Ctr Resp Med,State Key Lab Resp, Guangzhou 510120, Guangdong, Peoples R China; [Li, Xiaolan; Ran, Qin; He, Xiang; Peng, Dan; Xiong, Anying; Jiang, Manling; Zhang, Lei; Wang, Junyi; Bai, Lingling; Liu, Shengbin; Li, Guoping] Southwest Jiaotong Univ, Third Peoples Hosp Chengdu, Chengdu Inst Resp Hlth, Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610000, Peoples R China; [Li, Xiaolan; Ran, Qin; He, Xiang; Peng, Dan; Xiong, Anying; Jiang, Manling; Zhang, Lei; Wang, Junyi; Bai, Lingling; Liu, Shengbin; Li, Guoping] ChongQing Med Univ, Chengdu Third Peoples Hosp Branch, Dept Pulm & Crit Care Med, Natl Clin Res Ctr Resp Dis,Affiliated Hosp, Chengdu 610000, Peoples R China; [Li, Shiyue] Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou 510120, Peoples R China

通信作者：Sun, BQ (通讯作者)，Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis, Dept Clin Lab,Natl Ctr Resp Med,State Key Lab Resp, Guangzhou 510120, Guangdong, Peoples R China.; Li, GP (通讯作者)，Southwest Jiaotong Univ, Third Peoples Hosp Chengdu, Chengdu Inst Resp Hlth, Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610000, Peoples R China.; Li, SY (通讯作者)，Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou 510120, Peoples R China.

来源：ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001232245100001

JCR分区：Q1

影响因子：6.2

年份：2024

卷号：277

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：PM2.5; HO-1; Ferroptosis; Mitophagy; Neurotoxicity

摘要：Fine particulate matter (PM2.5) has been extensively implicated in the pathogenesis of neurodevelopmental disorders, but the underlying mechanism remains unclear. Recent studies have revealed that PM2.5 plays a role in regulating iron metabolism and redox homeostasis in the brain, which is closely associated with ferroptosis. In this study, the role and underlying mechanism of ferroptosis in PM2.5-induced neurotoxicity were investigated in mice, primary hippocampal neurons, and HT22 cells. Our findings demonstrated that exposure to PM2.5 could induce abnormal behaviors, neuroinflammation, and neuronal loss in the hippocampus of mice. These effects may be attributed to ferroptosis induced by PM2.5 exposure in hippocampal neurons. RNA-seq analysis revealed that the upregulation of iron metabolism -related protein Heme Oxygenase 1 (HO -1) and the activation of mitophagy might play key roles in PM2.5-induced ferroptosis in HT22 cells. Subsequent in vitro experiments showed that PM2.5 exposure significantly upregulated HO -1 in primary hippocampal neurons and HT22 cells. Moreover, PM2.5 exposure activated mitophagy in HT22 cells, leading to the loss of mitochondrial membrane potential, alterations in the expression of autophagy-related proteins LC3, P62, and mTOR, as well as an increase in mitophagy-related protein PINK1 and PARKIN. As a heme-degradation enzyme, the upregulation of HO -1 promotes the release of excess iron, genetically inhibiting the upregulation of HO -1 in HT22 cells could prevent both PM2.5-induced mitophagy and ferroptosis. Furthermore, pharmacological inhibition of mitophagy in HT22 cells reduced levels of ferrous ions and lipid peroxides, thereby preventing ferroptosis. Collectively, this study demonstrates that HO -1 mediates PM2.5-induced mitophagy-dependent ferroptosis in hippocampal neurons, and inhibiting mitophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following PM2.5 exposure.

基金机构：National Natural Science Foundation of China [82370022, 82370023, 82300088]; China Postdoctoral Science Foundation [2023M730799]; Natural Science Foundation of Sichuan Province [23NSFSC1736, 24NSFSC2826]; Chengdu Science and Technology Bureau [2021-YF09-00102-SN]; Chengdu High-level Key Clinical Specialty Construction Project [ZX20201202020]; Health Commission of Chengdu [2023269, 2023134]; Third People's Hospital of Chengdu Clinical Rechearch Program [CSY-YN-01-2023-048, CSY-YN-01-2023-024]

基金资助正文：This work was supported by the National Natural Science Foundation of China (82370022, 82370023, and 82300088) , China Postdoctoral Science Foundation (2023M730799) , Natural Science Foundation of Sichuan Province (23NSFSC1736 and 24NSFSC2826) , Chengdu Science and Technology Bureau (2021-YF09-00102-SN) , Chengdu High-level Key Clinical Specialty Construction Project (ZX20201202020) , Health Commission of Chengdu (2023134 and 2023269) , and The Third People's Hospital of Chengdu Clinical Rechearch Program (CSY-YN-01-2023-048 and CSY-YN-01-2023-024) .