Document Type
Article
Journal Title
Redox Biology
Publication Date
2-5-2013
Volume
1
Abstract
Manganese superoxide dismutase, encoded by the Sod2 gene, is a ubiquitously expressed mitochondrial antioxidant enzyme that is essential for mammalian life. Mice born with constitutive genetic knockout of Sod2 do not survive the neonatal stage, which renders the longitudinal study of the biochemical and metabolic effects of Sod2 loss difficult. However, multiple studies have demonstrated that tissue-specific knockout of Sod2 in murine liver yields no observable gross pathology or injury to the mouse. We hypothesized that Sod2 loss may have sub-pathologic effects on liver biology, including the acquisition of reactive oxygen species-mediated mitochondrial DNA mutations. To evaluate this, we established and verified a hepatocyte-specific knockout of Sod2 in C57/B6 mice using Cre-LoxP recombination technology. We utilized deep sequencing to identify possible mutations in Sod2 (-/-) mitochondrial DNA as compared to wt, and both RT-PCR and traditional biochemical assays to evaluate baseline differences in redox-sensitive pathways in Sod2 (-/-) hepatocytes. Surprisingly, no mutations in Sod2 (-/-) mitochondrial DNA were detected despite measurable increases in dihydroethidium staining in situ and concomitant decreases in complex II activity indicative of elevated superoxide in the Sod2 (-/-) hepatocytes. In contrast, numerous compensatory alterations in gene expression were identified that suggest hepatocytes have a remarkable capacity to adapt and overcome the loss of Sod2 through transcriptional means. Taken together, these results suggest that murine hepatocytes have a large reserve capacity to cope with the presence of additional mitochondrial reactive oxygen species.
DOI Link
ISSN
2213-2317
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Cyr, Anthony R.; Brown, Kyle E.; McCormick, Michael L.; Coleman, Mitchell C.; Case, Adam J.; Watts, George S.; Futscher, Bernard W.; Spitz, Douglas R.; and Domann, Frederick E., "Maintenance of mitochondrial genomic integrity in the absence of manganese superoxide dismutase in mouse liver hepatocytes." (2013). Journal Articles: Cellular & Integrative Physiology. 4.
https://digitalcommons.unmc.edu/com_cell_articles/4
Included in
Cellular and Molecular Physiology Commons, Medical Physiology Commons, Systems and Integrative Physiology Commons