Maintenance of mitochondrial genomic integrity in the absence of manganese superoxide dismutase in mouse liver hepatocytes

Anthony R Cyr; Kyle E Brown; Michael L McCormick; Mitchell C Coleman; Adam J Case; George S Watts; Bernard W Futscher; Douglas R Spitz; Frederick E Domann

doi:10.1016/j.redox.2013.01.001

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Maintenance of mitochondrial genomic integrity in the absence of manganese superoxide dismutase in mouse liver hepatocytes

Journal article

Open access

Peer reviewed

Maintenance of mitochondrial genomic integrity in the absence of manganese superoxide dismutase in mouse liver hepatocytes

Anthony R Cyr, Kyle E Brown, Michael L McCormick, Mitchell C Coleman, Adam J Case, George S Watts, Bernard W Futscher, Douglas R Spitz and Frederick E Domann

Redox biology, Vol.1(1), pp.172-177

2013

DOI: 10.1016/j.redox.2013.01.001

PMCID: PMC3757676

PMID: 24024150

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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.

SOD

Research Paper

Superoxide

Mitochondrial DNA

Redox compensation

Liver

Details

Title: Subtitle: Maintenance of mitochondrial genomic integrity in the absence of manganese superoxide dismutase in mouse liver hepatocytes
Creators: Anthony R Cyr - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kyle E Brown - Department of Internal Medicine, Gastroenterology Division, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA
Michael L McCormick - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Mitchell C Coleman - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Adam J Case - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
George S Watts - University of Arizona Cancer Center and Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA
Bernard W Futscher - University of Arizona Cancer Center and Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85724, USA
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Frederick E Domann - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Carver College of Medicine and the Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Redox biology, Vol.1(1), pp.172-177
DOI: 10.1016/j.redox.2013.01.001
PMID: 24024150
PMCID: PMC3757676
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier
Grant note: name: Arizona Cancer Center Shared Genomic Service. This work was supported by NIH, award: R01 CA115438, P30 CA086862, R01 CA133114, P42 ES004940
Language: English
Date published: 2013
Academic Unit: Gastroenterology and Hepatology; Pathology; Orthopedics and Rehabilitation; Surgery; Radiation Oncology; Internal Medicine
Record Identifier: 9984040385602771

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