{"title":"Neuroprotective Role of CHCHD2 in Parkinson's Disease: Insights into the GPX4-Related Ferroptosis Pathway.","authors":"Fang Wang, Xuanzhuo Liu, Mingyi Chen, Xiaoxin Xu, Ying Yang, Qiuhong Xu, Huili Zhu, Anding Xu, Mahmoud A Pouladi, Xiaohong Xu","doi":"10.1016/j.freeradbiomed.2024.11.034","DOIUrl":null,"url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by pathogenesis involving mitochondrial dysfunction, oxidative stress, and ferroptosis. Unfortunately, there are currently no effective interventions to slow down the progression of PD. The mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is implicated in neurodegeneration and serves as a biomarker for PD, has been reported to have neuroprotective effects against oxidative stress, but the potential molecular mechanisms involved remain elusive. In this study, we uncovered a critical mechanism by which CHCHD2 protected neuronal cells against oxidative stress with the ferroptosis pathway playing a pivotal role, as determined through tandem mass tags (TMT)-based proteomic analysis. The overexpression of CHCHD2 was observed to enhance cell viability, reduce levels of lipid peroxidation and reactive oxygen species (ROS), and upregulate the expression of the ferroptosis negative regulatory protein Glutathione peroxidase 4 (GPX4) in PD cells. Conversely, CHCHD2 knockdown led to reduced cell viability, elevated lipid peroxidation, and a decreased expression of GPX4. Additionally, CHCHD2 overexpression ameliorated motor function impairment, reduced α-synuclein levels, and mitigated dopaminergic (DA) neuron loss in the substantia nigra and striatum of PD mice. Importantly, we show that the inhibitory effect of CHCHD2 on ferroptosis in PD is related to the GPX4 signaling pathway. In summary, our study elucidates the neuroprotective role of CHCHD2 in regulating the GPX4-related ferroptosis pathway in PD, providing new targets and ideas for future PD drug development and therapy.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1000,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Biology and Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.freeradbiomed.2024.11.034","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by pathogenesis involving mitochondrial dysfunction, oxidative stress, and ferroptosis. Unfortunately, there are currently no effective interventions to slow down the progression of PD. The mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is implicated in neurodegeneration and serves as a biomarker for PD, has been reported to have neuroprotective effects against oxidative stress, but the potential molecular mechanisms involved remain elusive. In this study, we uncovered a critical mechanism by which CHCHD2 protected neuronal cells against oxidative stress with the ferroptosis pathway playing a pivotal role, as determined through tandem mass tags (TMT)-based proteomic analysis. The overexpression of CHCHD2 was observed to enhance cell viability, reduce levels of lipid peroxidation and reactive oxygen species (ROS), and upregulate the expression of the ferroptosis negative regulatory protein Glutathione peroxidase 4 (GPX4) in PD cells. Conversely, CHCHD2 knockdown led to reduced cell viability, elevated lipid peroxidation, and a decreased expression of GPX4. Additionally, CHCHD2 overexpression ameliorated motor function impairment, reduced α-synuclein levels, and mitigated dopaminergic (DA) neuron loss in the substantia nigra and striatum of PD mice. Importantly, we show that the inhibitory effect of CHCHD2 on ferroptosis in PD is related to the GPX4 signaling pathway. In summary, our study elucidates the neuroprotective role of CHCHD2 in regulating the GPX4-related ferroptosis pathway in PD, providing new targets and ideas for future PD drug development and therapy.
期刊介绍:
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.