Environmental neurotoxic pesticide exposure induces gut inflammation and enteric neuronal degeneration by impairing enteric glial mitochondrial function in pesticide models of Parkinson's disease: Potential relevance to gut-brain axis inflammation in Parkinson's disease pathogenesis. (June 2022)

• Record Type: Journal Article
• Authors: Palanisamy, Bharathi N.; Sarkar, Souvarish; Malovic, Emir; Samidurai, Manikandan; Charli, Adhithiya; Zenitsky, Gary; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G.
• Is Part Of: International journal of biochemistry & cell biology. Volume 147(2022)
• Publication Date: 2022-06
• Subjects: EGCs Enteric glial cells -- MFN2 Mitofusion 2 -- LC3 Microtubule-associated protein 1 A/1B-light chain 3 -- p62 ubiquitin-binding protein -- ENS Enteric nervous system -- TH Tyrosine hydroxylase -- GFAP Glial fibrillary acidic protein -- DMEM Dulbecco's modified eagle medium -- EDTA Ethylenediaminetetraacetic acid -- GDNF Glial cell line-derived neurotrophic factor -- PDL Poly-D-lysine -- HBSS Hank's balanced salt solution -- FCCP Trifluoromethoxy carbonylcyanide phenylhydrazone -- D2R Dopamine 2 receptor -- PGP9.5 Protein gene product 9.5 -- IRAC Insecticide resistance action committee; Rotenone -- Tebufenpyrad -- Enteric glial cells -- Enteric nervous system -- Reactive oxygen species -- Autophagy; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2022.106225
• Languages: English
• ISSNs: 1357-2725

Abstract

Abstract: 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.