Exposure to Mitochondrial Genotoxins and Dopaminergic Neurodegeneration in Caenorhabditis elegans

Gonzalez‐Hunt, Claudia P.; Leung, Maxwell C.K.; Bodhicharla, Rakesh; McKeever, Madeline G.; Arrant, Andrew E.; Margillo, Kathleen M.; Ryde, Ian T.; Cyr, Derek D.; Kosmaczewski, Sara Guckian; Hammarlund, Marc; Meyer, Joel N.

doi:10.1371/journal.pone.0114459

Cited by 75 publications

(53 citation statements)

References 119 publications

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“…However, UVC-induced mtDNA damage only caused larval growth arrest in fusion ( fzo-1, eat-3 )-deficient nematodes, suggesting that individuals with fusion deficiencies are more susceptible to toxicity induced by irreparable mtDNA damage. In agreement with this, we have also observed sensitivity to the mycotoxin aflatoxin B 1 and the chemotherapeutic cisplatin, both of which can cause irreparable mtDNA damage (González-Hunt et al 2014; Niranjan et al 1982; Podratz et al 2011), in fzo-1 - and eat-3 -deficient but not drp-1 C. elegans (Luz et al 2017). Although the precise reason for sensitivity to irreparable mtDNA damage in fusion-deficient C. elegans remains unknown, one possibility is the existence of a threshold effect in which >65% of mtDNA must typically be damaged or lost prior to pathogenesis (Taylor and Turnbull 2005).…”

Section: Gene-environment Interactions: How Does Genetic Variationsupporting

confidence: 87%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise.

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Section: Gene-environment Interactions: How Does Genetic Variationsupporting

confidence: 87%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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“…AfB 1 , a foodborne mycotoxin and important carcinogen in the developing world, causes bulky DNA lesions when its epoxide metabolite reacts with DNA. We and others have found that AfB 1 preferentially, and irreparably (due to a lack of NER) damages mtDNA [15–17]. Arsenite, a global drinking water contaminant associated with the development of skin, lung, and bladder cancer, is a well-known inhibitor of several Krebs cycle dehydrogenases [48], ETC complexes [49], and is also capable of causing metabolic shifts from OXPHOS to aerobic glycolysis, otherwise known as the Warburg effect [36, 50].…”

Section: Resultsmentioning

confidence: 99%

Effects of reduced mitochondrial DNA content on secondary mitochondrial toxicant exposure in Caenorhabditis elegans

Luz

Meyer

2016

Mitochondrion

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The mitochondrial genome (mtDNA) is intimately linked to cellular and organismal health, as demonstrated by the fact that mutations in and depletion of mtDNA result in severe mitochondrial disease in humans. However, cells contain hundreds to thousands of copies of mtDNA, which provides genetic redundancy, and creates a threshold effect in which a large percentage of mtDNA must be lost prior to clinical pathogenesis. As certain pharmaceuticals and genetic mutations can result in depletion of mtDNA, and as many environmental toxicants target mitochondria, it is important to understand whether reduced mtDNA will sensitize an individual to toxicant exposure. Here, using ethidium bromide (EtBr), which preferentially inhibits mtDNA replication, we reduced mtDNA 35-55% in the in vivo model organism Caenorhabditis elegans. Chronic, lifelong, low-dose EtBr exposure did not disrupt nematode development or lifespan, and induced only mild alterations in mitochondrial respiration, while having no effect on steady-state ATP levels. Next, we exposed nematodes with reduced mtDNA to the known and suspected mitochondrial toxicants aflatoxin B1, arsenite, paraquat, rotenone or ultraviolet C radiation (UVC). EtBr pre-exposure resulted in mild sensitization of nematodes to UVC and arsenite, had no effect on AfB1 and paraquat, and provided some protection from rotenone toxicity. These mixed results provide a first line of evidence suggesting that reduced mtDNA content may sensitize an individual to certain environmental exposures.

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“…We use 30 h of incubation time for all our experiments and encourage standardizing this time interval as starvation renders the animals more resistant to 6-OHDA treatment (González-Hunt et al , 2014; Offenburger et al , 2018b). After 30 h, several hundred L1s will accumulate in the wells, of which only around 200 will be used in the assay and only 50-100 randomly selected animals will be scored after treatment.…”

Section: Methodsmentioning

confidence: 99%

6-hydroxydopamine (6-OHDA) Oxidative Stress Assay for Observing Dopaminergic Neuron Loss in Caenorhabditis elegans

Offenburger¹,

Gartner²

2018

BIO-PROTOCOL

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The nematode Caenorhabditis elegans is a powerful genetic model that can be used to investigate neuronal death. Research using C. elegans has been crucial to characterize cell death programmes that are conserved in mammals. Many neuronal signaling components, such as those mediating dopaminergic neurotransmission, are preserved as well. Dopaminergic neurons are progressively lost in Parkinson’s disease and an important risk factor to develop this disease appears to be oxidative stress, the increased occurrence of highly reactive oxygen species. Oxidative stress-induced dopaminergic neurodegeneration is mimicked in animal models by treatment with 6-hydroxydopamine (6-OHDA), a dopamine analog, which is specifically taken up into dopaminergic neurons. After exposing C. elegans to 6-OHDA, the loss of fluorescently labeled dopaminergic neurons can be easily monitored. An organisms’ sensitivity to oxidative stress is thought to be influenced by basal levels of intrinsic oxidative stress and the ability to counteract oxidative stress and oxidative stress-induced damage. The C. elegans ‘6-OHDA model’ led to the discovery of novel genes that are required to protect dopaminergic neurons and it has helped to determine the effects of conserved cell death and cell engulfment pathways in dopaminergic neurodegeneration. Here, we describe a simple protocol that allows for the easy detection of dopaminergic neuron loss after 6-OHDA treatment in C. elegans.

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Exposure to Mitochondrial Genotoxins and Dopaminergic Neurodegeneration in Caenorhabditis elegans

Cited by 75 publications

References 119 publications

Mitochondrial fusion, fission, and mitochondrial toxicity

Mitochondrial fusion, fission, and mitochondrial toxicity

Effects of reduced mitochondrial DNA content on secondary mitochondrial toxicant exposure in Caenorhabditis elegans

6-hydroxydopamine (6-OHDA) Oxidative Stress Assay for Observing Dopaminergic Neuron Loss in Caenorhabditis elegans

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