Mitochondrial disease in superoxide dismutase 2 mutant mice

Mitochondrial disease in superoxide dismutase 2 mutant mice

^†Center for Molecular Medicine, Emory University, Atlanta, GA 30322; ^‡National Jewish Medical and Research Center, Denver, CO 80206; ^§Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226; ^¶National Institute of Standards and Technology, Gaithersburg, MD 20899; ^‖Department of Pediatrics, University of Colorado School of Medicine, Denver, CO 80262; and ^‡‡Division of Medical Genetics, University of California at San Francisco, San Francisco, CA 94143-0748

Contributed by Douglas C. Wallace

Abstract

Oxidative stress has been implicated in many diseases. The chief source of reactive oxygen species within the cell is the mitochondrion. We have characterized a variety of the biochemical and metabolic effects of inactivation of the mouse gene for the mitochondrial superoxide dismutase (CD1-Sod2 ^tm1Cje). The Sod2 mutant mice exhibit a tissue-specific inhibition of the respiratory chain enzymes NADH-dehydrogenase (complex I) and succinate dehydrogenase (complex II), inactivation of the tricarboxylic acid cycle enzyme aconitase, development of a urine organic aciduria in conjunction with a partial defect in 3-hydroxy-3-methylglutaryl-CoA lyase, and accumulation of oxidative DNA damage. These results indicate that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Footnotes

↵ †† To whom reprint requests should be addressed at: Center For Molecular Medicine, 1462 Clifton Road, Emory University, Atlanta, GA 30322. e-mail: dwallace{at}gmm.gen.emory.edu.
ABBREVIATIONS:

ROS,

reactive oxygen species;

OXPHOS,

oxidative phosphorylation;

SOD,

superoxide dismutase;

3-MGC,

3-methylglutaconic aciduria;

HMG,

3-hydroxy-3-methylglutaryl;

GC,

gas chromatography;

MS,

mass spectrometry;

IDMS,

isotope-dilution MS;

Ip,

iron–sulfur cluster-containing protein;

SDH,

succinate dehydrogenase;

IRE,

iron-regulatory elements