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Open AccessArticle

Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration

1
Nicholas School of the Environment, Duke University, Durham, NC 27708, USA
2
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Int. J. Mol. Sci. 2019, 20(13), 3202; https://doi.org/10.3390/ijms20133202
Received: 31 May 2019 / Revised: 24 June 2019 / Accepted: 26 June 2019 / Published: 29 June 2019
(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)
Background: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders involving devastating loss of dopaminergic neurons in the substantia nigra. Early steps in PD pathogenesis include mitochondrial dysfunction, and mutations in mitochondrial genes have been linked to familial forms of the disease. However, low penetrance of mutations indicates a likely important role for environmental factors in PD risk through gene by environment interactions. Herein, we study how genetic deficiencies in mitochondrial dynamics processes including fission, fusion, and mitophagy interact with environmental exposures to impact neurodegeneration. Methods: We utilized the powerful model organism Caenorhabditis elegans to study ultraviolet C radiation (UVC)- and 6-hydroxydopamine-induced degeneration of fluorescently-tagged dopaminergic neurons in the background of fusion deficiency (MFN1/2 homolog, fzo-1), fission deficiency (DMN1L homolog, drp-1), and mitochondria-specific autophagy (mitophagy) deficiency (PINK1 and PRKN homologs, pink-1 and pdr-1). Results: Overall, we found that deficiency in either mitochondrial fusion or fission sensitizes nematodes to UVC exposure (used to model common environmental pollutants) but protects from 6-hydroxydopamine-induced neurodegeneration. By contrast, mitophagy deficiency makes animals more sensitive to these stressors with an interesting exception—pink-1 deficiency conferred remarkable protection from 6-hydroxydopamine. We found that this protection could not be explained by compensatory antioxidant gene expression in pink-1 mutants or by differences in mitochondrial morphology. Conclusions: Together, our results support a strong role for gene by environment interactions in driving dopaminergic neurodegeneration and suggest that genetic deficiency in mitochondrial processes can have complex effects on neurodegeneration. View Full-Text
Keywords: mitochondrial fusion; mitochondrial fission; mitophagy; dopaminergic neurodegeneration; 6-hydroxydopamine; mitochondrial DNA damage mitochondrial fusion; mitochondrial fission; mitophagy; dopaminergic neurodegeneration; 6-hydroxydopamine; mitochondrial DNA damage
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Hartman, J.H.; Gonzalez-Hunt, C.; Hall, S.M.; Ryde, I.T.; Caldwell, K.A.; Caldwell, G.A.; Meyer, J.N. Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration. Int. J. Mol. Sci. 2019, 20, 3202.

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