Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans.

Claudia P González-Hunt,Andrew E Arrant,Ian T Ryde,Sara G Kosmaczewski,Kathleen M Margillo,Marc Hammarlund,Maxwell C K Leung,Joel N Meyer,Madeline G Mckeever,Derek D Cyr,Rakesh K Bodhicharla,Huaibin Cai

doi:10.1371/journal.pone.0114459

Claudia P González-Hunt, Andrew E Arrant + Show 10 more

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https://doi.org/10.1371/journal.pone.0114459

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Journal: PloS one	Publication Date: Dec 8, 2014
Citations: 67	License type: CC BY 4.0

Affiliation: Duke University, Yale University

Abstract

Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.

Highlights

The possible mitochondrial toxicity of environmental pollutants has attracted increasing interest in recent years [1,2,3,4], and mitochondrial DNA may represent a critical target
We first tested the ability of known neurotoxins or genotoxins to cause either mitochondrial or nuclear DNA damage
Our results show that the important environmental pollutants paraquat, AFB1 and CdCl2 can cause more mitochondrial DNA (mtDNA) than nDNA damage in the nematode C. elegans

Summary

Introduction

The possible mitochondrial toxicity of environmental pollutants has attracted increasing interest in recent years [1,2,3,4], and mitochondrial DNA (mtDNA) may represent a critical target. The high metabolic activity of neurons leads to the production of ROS, and the brain is susceptible to oxidative stress due to its low supply of antioxidant enzymes and high lipid content [28, 29]. A recent study showed dopaminergic neurodegeneration in mice exhibiting mtDNA doublestrand breaks produced by a mitochondrial-targeted restriction enzyme [38]. Another recent study detected oxidative mtDNA lesions in the brain of Parkinson’s disease (PD) patients, and in vivo and in vitro after mitochondrial impairment by rotenone [39]. Mutations in the only mtDNA polymerase, DNA polymerase c, can result in parkinsonism in humans [40, 41]

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