Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans

Hershberger, Kathleen A.; Rooney, John P.; Turner, Elena A.; Donoghue, Lauren J.; Bodhicharla, Rakesh; Maurer, Laura L.; Ryde, Ian T.; Kim, Jina J.; Joglekar, Rashmi; Hibshman, Jonathan D.; Smith, Latasha L.; Bhatt, Dhaval P.; Hirschey, Matthew D.; Meyer, Joel N.

doi:10.1016/j.redox.2021.102000

Cited by 19 publications

(12 citation statements)

References 86 publications

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“…Growth involves biological processes which require high levels of mitochondrially-derived energy. Conversely, at early developmental stages several mitochondrial parameters are limited or greatly reduced, promoting great sensitivity to mitochondrial toxicants in early life stages. − Moreover, because mitochondrial parameters and function are highly variable with the developmental stage, there may be developmental windows of susceptibility to mitochondrial toxicants. , Thus, we hypothesized that if AgNPs were impairing mitochondrial function, we would be able to observe a dose-dependent growth inhibition in developing nematodes.…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, these parameters may also be influenced by other mechanisms including redox signaling and oxidative stress. C. elegans development is highly dependent on ROS levels and related signaling pathways, 32,71 and neurons of vertebrate species are highly dependent on hydrogen sulfide and antioxidant pools. 68 These findings, together with our results, are in line with the role of AgNPs in causing growth, development, and behavior of AOs (Figure 4).…”

Section: Nanoparticle Synthesis and Characterizationmentioning

confidence: 99%

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In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics

Mello

Maurer

Ryde

et al. 2022

Environ. Sci. Technol.

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Silver nanoparticles (AgNPs) are extensively used in consumer products and biomedical applications, thus guaranteeing both environmental and human exposures. Despite extensive research addressing AgNP safety, there are still major knowledge gaps regarding AgNP toxicity mechanisms, particularly in whole organisms. Mitochondrial dysfunction is frequently described as an important cytotoxicity mechanism for AgNPs; however, it is still unclear if mitochondria are the direct targets of AgNPs. To test this, we exposed the nematodeCaenorhabditis elegans to sublethal concentrations of AgNPs and assessed specific mitochondrial parameters as well as organismal-level endpoints that are highly reliant on mitochondrial function, such as development and chemotaxis behavior. All AgNPs tested significantly delayed nematode development, disrupted mitochondrial bioenergetics, and blocked chemotaxis. However, silver was not preferentially accumulated in mitochondria, indicating that these effects are likely not due to direct mitochondria–AgNP interactions. Mutant nematodes with deficiencies in mitochondrial dynamics displayed both greater and decreased susceptibility to AgNPs compared to wild-type nematodes, which was dependent on the assay and AgNP type. Our study suggests that AgNPs indirectly promote mitochondrial dysfunction, leading to adverse outcomes at the organismal level, and reveals a role of gene–environment interactions in the susceptibility to AgNPs. Finally, we propose a novel hypothetical adverse outcome pathway for AgNP effects to guide future research.

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Section: Resultsmentioning

confidence: 99%

Section: Nanoparticle Synthesis and Characterizationmentioning

confidence: 99%

In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics

Mello

Maurer

Ryde

et al. 2022

Environ. Sci. Technol.

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“…were reset during the GW. There is strong evidence from various animal model systems for mitochondrial stressors resulting in long-term alterations in mitochondrial function [119][120][121][122]; an important future direction would be to interrogate mechanisms such as epigenetic patterning [123] that could mediate persistently altered mitochondrial function.…”

Section: Plos Onementioning

confidence: 99%

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Meyer,

Pan,

Ryde

et al. 2023

PLoS ONE

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Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

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“…In this study, we opted to perform a developmental rotenone exposure because, at this stage, animals are usually more sensitive to mitochondrial toxicants. This greater sensitivity is because while early developmental stages and growth involve biological processes which require high levels of mitochondrially-derived energy, at these stages, several mitochondrial parameters are limited or greatly reduced (49)(50)(51)(52)(53). Moreover, mitochondrial parameters and function are highly variable with developmental stage; thus, it is likely that mitochondrial toxicants can have more profound effects on some developmental windows of susceptibility (14,41).…”

Section: Discussionmentioning

confidence: 99%

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

et al. 2022

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Mitochondria are central players in host immunometabolism as they function not only as metabolic hubs but also as signaling platforms regulating innate immunity. Environmental exposures to mitochondrial toxicants occur widely and are increasingly frequent. Exposures to these mitotoxicants may pose a serious threat to organismal health and the onset of diseases by disrupting immunometabolic pathways. In this study, we investigated whether the Complex I inhibitor rotenone could alter C. elegans immunometabolism and disease susceptibility. C. elegans embryos were exposed to rotenone (0.5 µM) or DMSO (0.125%) until they reached the L4 larval stage. Inhibition of mitochondrial respiration by rotenone and disruption of mitochondrial metabolism were evidenced by rotenone-induced detrimental effects on mitochondrial efficiency and nematode growth and development. Next, through transcriptomic analysis, we investigated if this specific but mild mitochondrial stress that we detected would lead to the modulation of immunometabolic pathways. We found 179 differentially expressed genes (DEG), which were mostly involved in detoxification, energy metabolism, and pathogen defense. Interestingly, among the down-regulated DEG, most of the known genes were involved in immune defense, and most of these were identified as commonly upregulated during P. aeruginosa infection. Furthermore, rotenone increased susceptibility to the pathogen Pseudomonas aeruginosa (PA14). However, it increased resistance to Salmonella enterica (SL1344). To shed light on potential mechanisms related to these divergent effects on pathogen resistance, we assessed the activation of the mitochondrial unfolded protein response (UPRmt), a well-known immunometabolic pathway in C. elegans which links mitochondria and immunity and provides resistance to pathogen infection. The UPRmt pathway was activated in rotenone-treated nematodes further exposed for 24 h to the pathogenic bacteria P. aeruginosa and S. enterica or the common bacterial food source Escherichia coli (OP50). However, P. aeruginosa alone suppressed UPRmt activation and rotenone treatment rescued its activation only to the level of DMSO-exposed nematodes fed with E. coli. Module-weighted annotation bioinformatics analysis was also consistent with UPRmt activation in rotenone-exposed nematodes consistent with the UPR being involved in the increased resistance to S. enterica. Together, our results demonstrate that the mitotoxicant rotenone can disrupt C. elegans immunometabolism in ways likely protective against some pathogen species but sensitizing against others.

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Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans

Cited by 19 publications

References 86 publications

In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics

In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

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