线粒体
生物
肠神经系统
生物能学
线粒体呼吸链
小胶质细胞
氧化应激
鱼藤酮
帕金森病
炎症
细胞生物学
神经毒性
MFN2型
神经退行性变
呼吸链
免疫学
线粒体融合
病理
神经科学
生物化学
线粒体DNA
内科学
医学
毒性
疾病
基因
作者
Bharathi N. Palanisamy,Souvarish Sarkar,Emir Malovic,Manikandan Samidurai,Adhithiya Charli,Gary Zenitsky,Huajun Jin,Vellareddy Anantharam,Anumantha G. Kanthasamy,Anumantha G. Kanthasamy
标识
DOI:10.1016/j.biocel.2022.106225
摘要
Despite the growing recognition that gastrointestinal (GI) dysfunction is prevalent in Parkinson's disease (PD) and occurs as a major prodromal symptom of PD, its cellular and molecular mechanisms remain largely unknown. Among the various types of GI cells, enteric glial cells (EGCs), which resemble astrocytes in structure and function, play a critical role in the pathophysiology of many GI diseases including PD. Thus, we investigated how EGCs respond to the environmental pesticides rotenone (Rot) and tebufenpyrad (Tebu) in cell and animal models to better understand the mechanism underlying GI abnormalities. Both Rot and Tebu induce dopaminergic neuronal cell death through complex 1 inhibition of the mitochondrial respiratory chain. We report that exposing a rat enteric glial cell model (CRL-2690 cells) to these pesticides increased mitochondrial fission and reduced mitochondrial fusion by impairing MFN2 function. Furthermore, they also increased mitochondrial superoxide generation and impaired mitochondrial ATP levels and basal respiratory rate. Measurement of LC3, p62 and lysosomal assays revealed impaired autolysosomal function in ECGs during mitochondrial stress. Consistent with our recent findings that mitochondrial dysfunction augments inflammation in astrocytes and microglia, we found that neurotoxic pesticide exposure also enhanced the production of pro-inflammatory factors in EGCs in direct correlation with the loss in mitochondrial mass. Finally, we show that pesticide-induced mitochondrial defects functionally impaired smooth muscle velocity, acceleration, and total kinetic energy in a mixed primary culture of the enteric nervous system (ENS). Collectively, our studies demonstrate for the first time that exposure to environmental neurotoxic pesticides impairs mitochondrial bioenergetics and activates inflammatory pathways in EGCs, further augmenting mitochondrial dysfunction and pro-inflammatory events to induce gut dysfunction. Our findings have major implications in understanding the GI-related pathogenesis and progression of environmentally linked PD.
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