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HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons
Xiaolan Li1, Qin Ran2, Xiang He1
1Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, China.
Abstract:
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.
Insights
Fine particulate matter (PM2.5) exposure causes neurotoxicity by inducing ferroptosis, a cell death pathway. Heme oxygenase 1 (HO-1) and mitophagy are key mechanisms driving this process in brain cells.
Area of Science:
- Neuroscience
- Environmental Health
- Cell Biology
Background:
- Fine particulate matter (PM2.5) is linked to neurodevelopmental disorders, but mechanisms are unclear.
- PM2.5 affects brain iron metabolism and redox balance, potentially inducing ferroptosis.
- Ferroptosis is an iron-dependent cell death pathway implicated in various neurological conditions.
Purpose of the Study:
- Investigate the role of ferroptosis in PM2.5-induced neurotoxicity.
- Elucidate the underlying molecular mechanisms, including iron metabolism and mitophagy.
- Assess potential therapeutic targets for mitigating PM2.5 neurotoxicity.
Main Methods:
- Utilized mouse models, primary hippocampal neurons, and HT22 cells for in vitro and in vivo studies.
- Employed RNA-sequencing (RNA-seq) to identify key molecular pathways.
- Applied genetic inhibition and pharmacological treatments to investigate ferroptosis and mitophagy.
Main Results:
- PM2.5 exposure induced abnormal behaviors, neuroinflammation, and neuronal loss in mice.
- PM2.5 upregulated Heme Oxygenase 1 (HO-1) and activated mitophagy in hippocampal neurons and HT22 cells.
- Inhibition of HO-1 or mitophagy prevented PM2.5-induced ferroptosis and neurotoxicity.
Conclusions:
- PM2.5 induces mitophagy-dependent ferroptosis in hippocampal neurons via HO-1.
- Targeting mitophagy or ferroptosis presents a promising therapeutic strategy against PM2.5 neurotoxicity.
