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

Abstract

BackgroundMitochondrial 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.MethodsWe 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.ResultsAlthough 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.ConclusionsThese 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.

Mitochondrial fusion, fission, and mitochondrial toxicity

“…Interestingly, the same has been reported for low levels of some mitotoxicants, such as arsenic (Schmeisser et al 2013); however, we recently found that concentrations of arsenic that were harmless or even beneficial in wild-type Caenorhabditis elegans were instead toxic to fusion-deficient individuals (Luz et al 2017). On the other hand, some mitochondrial perturbations can have persistent, deleterious consequences (Berthiaume and Wallace 2007a, b; Chan et al 2007; Ditzel et al 2015; Divi et al 2010; Leung et al 2013; Saben et al 2016; Wood et al 2015), and thus may contribute the developmental origins of adult health and disease. Testing this possibility will be an additional, important future direction, especially given the very different mitochondrial morphologies and functions observed in early-stage organisms and undifferentiated cells.…”

Mitochondrial DNA damage induced autophagy cell death and disease

“…We carried out experiments in the nematode Caenorhabditis elegans to test the effect of persistent mtDNA damage, using a protocol that resulted in the accumulation of high levels of mtDNA photoproducts while allowing for the repair of most of the simultaneously induced nDNA damage (39, 40). This damage was generated by UV exposure in the first of the four larval stages of the organism.…”

“…This damage was generated by UV exposure in the first of the four larval stages of the organism. The irradiation resulted in lower levels of mtDNA (i.e., lower mtDNA copy number per cell), lower levels of ATP, lower levels of oxygen consumption, and dose-responsive inhibition of larval development (39, 40). The mRNA levels for mtDNA-encoded proteins were initially lower than in unexposed nematodes, but later rebounded (40).…”

OMICS as Therapeutic Platform: Environmental Factors to Parkinson’s Disease

“…They are essentially the power house of the cell by producing ATP as a driving fuel for the cells [11]. Interestingly, the mitochondria are the focal point for idiopathic diseases and genetic diseases due to their sensitivity to environmental insult.…”