Mitochondrial dynamics and autophagy aid in removal of persistent mitochondrial DNA damage in Caenorhabditis elegans.

Mitochondria lack the ability to repair certain helix-distorting lesions that are induced at high levels in mitochondrial DNA (mtDNA) by important environmental genotoxins and endogenous metabolites. These lesions are irreparable and persistent in the short term, but their long-term fate is unknown. We report that removal of such mtDNA damage is detectable by 48 h in Caenorhabditis elegans, and requires mitochondrial fusion, fission and autophagy, providing genetic evidence for a novel mtDNA damage removal pathway. Furthermore, mutations in genes involved in these processes as well as pharmacological inhibition of autophagy exacerbated mtDNA damage-mediated larval arrest, illustrating the in vivo relevance of removal of persistent mtDNA damage. Mutations in genes in these pathways exist in the human population, demonstrating the potential for important gene-environment interactions affecting mitochondrial health after genotoxin exposure.

UVC-induced mitochondrial degradation via autophagy correlates with mtDNA damage removal in primary human fibroblasts.

Mitochondrial DNA (mtDNA) is more susceptible than nuclear DNA to helix-distorting damage via exposure to environmental genotoxins, partially due to a lack of nucleotide excision repair. Thus, this damage is irreparable and persistent in mtDNA in the short term. We recently found that helix-distorting mtDNA damage induced by ultraviolet C radiation (UVC) is gradually removed in Caenorhabditis elegans and that removal is dependent upon autophagy and mitochondrial dynamics. We here report the effects of UVC exposure on mitophagy, mitochondrial morphology, and indicators of mitochondrial function in mammalian cells. Exposure to UVC induced autophagy within 24 h; nonetheless, significant mitochondrial degradation was not observed until 72 h post exposure. Mitochondrial mass, morphology, and function were not significantly altered. These data further support the idea that persistent mtDNA damage is removed by autophagy and also suggest a powerful compensatory capacity for dealing with mtDNA damage.

Review of Polycyclic Aromatic Hydrocarbons (PAHs) Sediment Quality Guidelines for the Protection of Benthic Life.

Polycyclic aromatic hydrocarbons (PAHs) in sediments can pose harm to the benthic community. Numerous sediment quality guidelines (SQGs) for the protection of benthic life are available to assess the risk of individual PAHs and PAH mixtures in sediments. Sediment quality guidelines are derived using empirical or mechanistic approaches. Empirically based guidelines are derived using databases of paired sediment chemistry and biological responses and relating sediment concentration to the frequency of an adverse response. Mechanistically based SQGs are derived by considering the inherent aqueous toxicity of the chemical to different biota coupled with site-specific sediment characteristics (i.e., organic C) known to influence PAH bioavailability. Additionally, SQGs are derived to be either protective or predictive of adverse effects in benthic organisms. The objective of this critical review was to evaluate SQGs for use in screening-level risk assessments to identify sediments that may pose a risk to the benthic community. SQGs for PAHs were compiled and compared, and performance evaluated for predicting the presence and absence of toxicity using an extensive field data set. Furthermore, a 2-carbon equilibrium partitioning model and direct measurement of porewater via passive sampling were evaluated for improved performance in higher tiered risk assessments. Recommendations for the use of SQGs in screening evaluations, enhancements to current approaches, and opportunities to refine site risk estimate assessments using passive sampling measurements are discussed. Integr Environ Assess Manag 2019;15:505-518. © 2019 SETAC.

Effects of mutations in mitochondrial dynamics-related genes on the mitochondrial response to ultraviolet C radiation in developing Caenorhabditis elegans.

We recently found that genes involved in mitochondrial dynamics and autophagy are required for removal of UVC-induced mitochondrial DNA damage. However, drp-1 and pink-1, unlike the autophagy and fusion genes tested, were not necessary for larval development after exposure. We hypothesized that increased fusion resulting from mutations in these genes facilitated recovery of mitochondrial function. In this work, we investigated this hypothesis by studying the effects of fis-1, fis-2, drp-1 and pink-1 mutations on mitochondrial responses to UVC exposure including ATP levels, mitochondrial DNA copy number, larval development and mitochondrial morphology. Our results suggest that mutations that promote highly networked mitochondria have the capacity to lessen the effects of mitochondrial genotoxicants on the function of this organelle.

Mitochondria as a target of environmental toxicants.

Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria.

Effects of early life exposure to ultraviolet C radiation on mitochondrial DNA content, transcription, ATP production, and oxygen consumption in developing Caenorhabditis elegans.

BACKGROUND: Mitochondrial DNA (mtDNA) is present in multiple copies per cell and undergoes dramatic amplification during development. The impacts of mtDNA damage incurred early in development are not well understood, especially in the case of types of mtDNA damage that are irreparable, such as ultraviolet C radiation (UVC)-induced photodimers. METHODS: We exposed first larval stage nematodes to UVC using a protocol that results in accumulated mtDNA damage but permits nuclear DNA (nDNA) repair. We then measured the transcriptional response, as well as oxygen consumption, ATP levels, and mtDNA copy number through adulthood. RESULTS: Although the mtDNA damage persisted to the fourth larval stage, we observed only a relatively minor ~40% decrease in mtDNA copy number. Transcriptomic analysis suggested an inhibition of aerobic metabolism and developmental processes; mRNA levels for mtDNA-encoded genes were reduced ~50% at 3 hours post-treatment, but recovered and, in some cases, were upregulated at 24 and 48 hours post-exposure. The mtDNA polymerase γ was also induced ~8-fold at 48 hours post-exposure. Moreover, ATP levels and oxygen consumption were reduced in response to UVC exposure, with marked reductions of ~50% at the later larval stages. CONCLUSIONS: These results support the hypothesis that early life exposure to mitochondrial genotoxicants could result in mitochondrial dysfunction at later stages of life, thereby highlighting the potential health hazards of time-delayed effects of these genotoxicants in the environment.

Involvement of autophagy and mitochondrial dynamics in determining the fate and effects of irreparable mitochondrial DNA damage.

Mitochondrial DNA (mtDNA) is different in many ways from nuclear DNA. A key difference is that certain types of DNA damage are not repaired in the mitochondrial genome. What, then, is the fate of such damage? What are the effects? Both questions are important from a health perspective because irreparable mtDNA damage is caused by many common environmental stressors including ultraviolet C radiation (UVC). We found that UVC-induced mtDNA damage is removed slowly in the nematode Caenorhabditis elegans via a mechanism dependent on mitochondrial fusion, fission, and autophagy. However, knockdown or knockout of genes involved in these processes­many of which have homologs involved in human mitochondrial diseases­had very different effects on the organismal response to UVC. Reduced mitochondrial fission and autophagy caused no or small effects, while reduced mitochondrial fusion had dramatic effects.