Authors: Longo VD; Liou LL; Valentine JS; Gralla EB
Abstract: Yeast lacking mitochondrial superoxide dismutase (MnSOD) display shortened stationary-phase survival and provide a good model system for studying mitochondrial oxidative damage. We observed a marked decrease in respiratory function preceding stationary-phase death of yeast lacking MnSOD (sod2Delta). Agents (mitochondrial inhibitors) that are known to increase or decrease superoxide production in submitochondrial particles affected stationary-phase survival in a manner inversely correlated with their effects on superoxide production, implicating superoxide in this mitochondrial disfunction. Similar but less-dramatic effects were observed in wild-type yeast. The activities of certain mitochondrial enzymes were particularly affected. In sod2Delta yeast the activity of aconitase, a 4Fe-4S-cluster-containing enzyme located in the matrix, was greatly and progressively decreased as the cells established stationary phase. Succinate dehydrogenase activity also decreased in MnSOD mutants; cytochrome oxidase and ATPase activities did not. Aconitase could be reactivated by addition of materials required for cluster assembly (Fe3+ and a sulfur source), both in extracts and in vivo, indicating that inactivation of the enzyme was by disassembly of the cluster. Our results support the conclusion that superoxide is generated in the mitochondria in vivo and under physiological conditions and that MnSOD is the primary defense against this toxicity. When the balance between superoxide generation and MnSOD activity is disrupted, superoxide mediates iron release from mitochondrial iron-sulfur clusters, leading first to loss of mitochondrial function and then to death, independently of mtDNA damage. These results raise the possibility that similar processes may occur in higher eukaryotes.
Keywords: Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology; Cell Compartmentation; Cell Death; DNA Damage; Enzyme Inhibitors/pharmacology; Hydro-Lyases/metabolism; Iron-Sulfur Proteins/metabolism; Mitochondria/*metabolism; Mutagens; Mutation; *Oxygen Consumption; Saccharomyces cerevisiae/*cytology/metabolism; Sodium Cyanide/pharmacology; Superoxide Dismutase/genetics/*metabolism; Superoxides/*toxicity|
Journal: Archives of biochemistry and biophysics Volume: 365 Issue: 1 Pages: 131-42 Date: May 1, 1999 PMID: 10222047 |
Longo VD, Liou LL, Valentine JS, Gralla EB (1999) Mitochondrial superoxide decreases yeast survival in stationary phase. Archives of biochemistry and biophysics 365: 131-42.
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