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Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans
- Source :
- Redox Biology, Vol 43, Iss, Pp 102000-(2021), Redox Biology
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- The consequences of damage to the mitochondrial genome (mtDNA) are poorly understood, although mtDNA is more susceptible to damage resulting from some genotoxicants than nuclear DNA (nucDNA), and many environmental toxicants target the mitochondria. Reports from the toxicological literature suggest that exposure to early-life mitochondrial damage could lead to deleterious consequences later in life (the “Developmental Origins of Health and Disease” paradigm), but reports from other fields often report beneficial (“mitohormetic”) responses to such damage. Here, we tested the effects of low (causing no change in lifespan) levels of ultraviolet C (UVC)-induced, irreparable mtDNA damage during early development in Caenorhabditis elegans. This exposure led to life-long reductions in mtDNA copy number and steady-state ATP levels, accompanied by increased oxygen consumption and altered metabolite profiles, suggesting inefficient mitochondrial function. Exposed nematodes were also developmentally delayed, reached smaller adult size, and were rendered more susceptible to subsequent exposure to chemical mitotoxicants. Metabolomic and genetic analysis of key signaling and metabolic pathways supported redox and mitochondrial stress-response signaling during early development as a mechanism for establishing these persistent alterations. Our results highlight the importance of early-life exposures to environmental pollutants, especially in the context of exposure to chemicals that target mitochondria.<br />Graphical abstract Image 1<br />Highlights • Early life mtDNA damage led to lifelong deficits in mitochondrial function. • C. elegans developed slowly and were sensitive to chemical exposures as adults. • Redox signaling is a mechanism that establishes these persistent alterations. • Data are consistent with the Developmental Origins of Health and Disease model.
- Subjects :
- 0301 basic medicine
Mitochondrial DNA
Medicine (General)
Redox signaling
Bioenergetics
QH301-705.5
Clinical Biochemistry
Mitochondrial DNA damage
Context (language use)
Mitochondrion
Biochemistry
DNA, Mitochondrial
03 medical and health sciences
Environmental toxicants
0302 clinical medicine
R5-920
Animals
Biology (General)
Caenorhabditis elegans
chemistry.chemical_classification
Reactive oxygen species
biology
Organic Chemistry
biology.organism_classification
Nuclear DNA
Cell biology
Mitochondria
Metabolic pathway
030104 developmental biology
chemistry
Developmental exposures
Mitochondrial function
Oxidation-Reduction
030217 neurology & neurosurgery
Research Paper
DNA Damage
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....ce215d55b22246f4d6d3e31744c87464