Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice

Melissa D. Williams, Holly Van Remmen, Craig C. Conrad, Ting Ting Huang, Charles J. Epstein, Arlan Richardson

Research output: Contribution to journalArticle

377 Citations (Scopus)

Abstract

This study characterizes mitochondria isolated from livers of Sod2-(- /+) and Sod2(+/+) mice. A 50% decrease in manganese superoxide dismutase (MnSOD) activity was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice, with no change in the activities of either glutathione peroxidase or copper/zinc superoxide dismutase. However, the level of total glutathione was 30% less in liver mitochondria of the Sod2(- /+) mice. The reduction in MnSOD activity in Sod2(-/+) mice was correlated to an increase in oxidative damage to mitochondria: decreased activities of the Fe-S proteins (aconitase and NADH oxidoreductase), increased carbonyl groups in proteins, and increased levels of 8-hydroxydeoxyguanosine in mitochondrial DNA. In contrast, there were no significant changes in oxidative damage in the cytosolic proteins or nuclear DNA. The increase in oxidative damage in mitochondria was correlated to altered mitochondrial function. A significant decrease in the respiratory control ratio was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice for substrates metabolized by complexes I, II, and III. In addition, mitochondria isolated from Sod2(-/+) mice showed an increased rate of induction of the permeability transition. Therefore, this study provides direct evidence correlating reduced MnSOD activity in vivo to increased oxidative damage in mitochondria and alterations in mitochondrial function.

Original languageEnglish (US)
Pages (from-to)28510-28515
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number43
DOIs
StatePublished - Oct 23 1998

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Mitochondria
Knockout Mice
Superoxide Dismutase
Liver Mitochondrion
Liver
Aconitate Hydratase
Protein S
Glutathione Peroxidase
Nuclear Proteins
Mitochondrial DNA
NAD
Glutathione
Zinc
Copper
Permeability
Oxidoreductases
Proteins
DNA
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. / Williams, Melissa D.; Van Remmen, Holly; Conrad, Craig C.; Huang, Ting Ting; Epstein, Charles J.; Richardson, Arlan.

In: Journal of Biological Chemistry, Vol. 273, No. 43, 23.10.1998, p. 28510-28515.

Research output: Contribution to journalArticle

Williams, Melissa D. ; Van Remmen, Holly ; Conrad, Craig C. ; Huang, Ting Ting ; Epstein, Charles J. ; Richardson, Arlan. / Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. In: Journal of Biological Chemistry. 1998 ; Vol. 273, No. 43. pp. 28510-28515.
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