Mitochondrial disease in superoxide dismutase 2 mutant mice

Melov, Simon; Coşkun, Pınar; Patel, Manisha; Tuinstra, Robbyn L.; Cottrell, Barbara A.; Jun, Albert S.; Zastawny, Tomsz H.; Dizdaroğlu, Miral; Goodman, Stephen I.; Huang, Ting; Miziorko, Henry M.; Epstein, Charles J.; Wallace, Douglas C.

doi:10.1073/pnas.96.3.846

Cited by 532 publications

(362 citation statements)

References 71 publications

Supporting

Mentioning

342

Contrasting

Unclassified

Order By: Relevance

“…For these experiments, we compared cultured DRG neurons from adult mice with full SOD2 expression (SOD2 +/+ ) to DRG from mice heterozygous for SOD2 expression (SOD2 +/− ). Mice homozygous for SOD2 knockout (SOD2 −/ − ) could not be used as these mice die shortly after birth with severe mitochondrial abnormalities in skeletal and cardiac muscle and brain (Lebovitz et al, 1996;Li et al, 1995;Melov et al, 1999). As anticipated, under basal culture conditions, increased levels of O 2 − • and cleaved caspase-3 were present in DRG neurons from SOD2+/− mice when compared to neurons from SOD2 +/+ mice.…”

Section: Discussionmentioning

confidence: 99%

“…Our results are broadly supported by over a decade of research in SOD2 +/− and SOD2 −/ − mice. While the homozygous SOD2 −/ − mice die shortly after birth (Lebovitz et al, 1996;Li et al, 1995;Melov et al, 1999), the heterozygous SOD2 +/− mice develop normally, but have increased susceptibility to toxic injury and prooxidant stress. For example, while the mitochondrial toxin 3-nitropropionic acid increases striatal excitotoxicity and oxidative stress in mouse models of Huntington's disease, these effects are amplified in Huntington SOD2 +/− transgenic mice (Kim and Chan, 2002).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

View full text Add to dashboard Cite

Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that over expression of SOD2 decreases superoxide (O 2 •− ) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Under expression of SOD2 in dissociated DRG cultures from adult SOD2 +/− mice results in increased levels of O 2 •− , activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2 +/− C57BL/6J mice and their SOD2 +/+ litter mates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

105

View full text Add to dashboard Cite

show abstract

“…These results suggest that at least in liver tissue, dwarf mice are subjected to less oxidative stress and may need less 02 to control membrane leakiness when compared to normal mice (7). In addition, while chronic exposure to ROS can result in oxidative damage to protein, lipids and DNA, acute exposure can inactivate electron transport chain complexes (I, II, III) resulting in reduced mitochondrial energy production (34,35). We have preliminary evidence indicating that in fact, protein levels of Complexes I, II and V are elevated in dwarf mice (36).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

Brown‐Borg

Johnson

Rakoczy

et al. 2001

AGE

View full text Add to dashboard Cite

Aging is associated with an accumulation of oxidative damage to proteins, lipids and DNA. Cellular mechanisms designed to prevent oxidative damage decline with aging and in diseases associated with aging. A long-lived mouse, the Ames dwarf, exhibits growth hormone deficiency and heightened antioxidative defenses. In contrast, animals that over express GH have suppressed antioxidative capacity and live half as long as wild type mice. In this study, we examined the generation of H202 from liver mitochondria of Ames dwarf and wild type mice and determined the level of oxidative damage to proteins, lipids and DNA in various tissues of these animals. Dwarf liver mitochondria (24 months) produced less H202 than normal liver in the presence of succinate (p<0.03) andADP (p<0.003). Levels of oxidative DNA damage (8OHdG) were variable and dependent on tissue and age in dwarf and normal mice. Forty-seven percent fewer protein carbonyls were detected in 24-month old dwarf liver tissue compared to controls (p<0.04). Forty percent more (p<0.04) protein carbonyls were detected in liver tissue (3-month old) of GH transgenic mice compared to wild types while 12 month old brain tissue had 53% more protein carbonyls compared to controls (p<0.005). Levels of liver malonaldehyde (lipid peroxidation) were not different at 3 and 12 months of age but were greater in Ames dwarf mice at 24 months compared to normal mice. Previous studies indicate a strong negative correla-

show abstract

“…Mitochondria contain Mn-superoxide dismutase (SOD-2) and glutathione peroxidase (GPx). The effect of knock-out of the SOD-2 gene in transgenic mice is dramatic, with inability to survive for more than 2 weeks after birth and development of a series of biochemical defects ascribed to oxidative stress (2). Similarly, the lack of mitochondrial GPx is deleterious in that the accumulation of hydrogen peroxide in presence of reduced metal ions leads to the extremely toxic hydroxyl radical (3): formation of OH ?…”

Section: Introductionmentioning

confidence: 99%

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

2001

View full text Add to dashboard Cite

SummaryMitochondria are major sources of reactive oxygen species (ROS); the main sites of superoxide radical production in the respiratory chain are Complexes III and I; however, other mitochondrial enzymes, such as Complex II, glycerol-1-phosphate dehydrogenase, and dihydroorotate dehydrogenase, are also involved in production of ROS. ROS appear to be released both in the matrix and in the intermembrane space; however, their appearance outside the mitochondria may not be physiologically relevant. ROS production is increased in State 4 and in all conditions when the respiratory components are substantially in the reduced form. Accordingly, defects inducing decrease of electron transfer in the respiratory chain, as in many pathological conditions, are bound to enhance ROS production.

show abstract

Mitochondrial disease in superoxide dismutase 2 mutant mice

Cited by 532 publications

References 71 publications

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

Contact Info

Product

Resources

About