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D-penicillamine-induced copper deficiency in suckling mice: neurological abnormalities and brain mitochondrial enzyme
M Yamamoto1, C Akiyama, H Aikawa
1Division of Ultrastructural Research, National Institute of Neuroscience, Tokyo, Japan.
Insights
D-penicillamine (DP) treatment in mice caused copper deficiency, leading to reduced brain cytochrome c oxidase activity. This study presents a valuable animal model for Menkes
Area of Science:
- Neuroscience
- Biochemistry
- Toxicology
Background:
- Copper is essential for various enzymatic functions in the brain.
- D-penicillamine (DP) is a chelating agent that can induce copper deficiency.
- Menkes' kinky hair disease and mitochondrial encephalomyopathies involve neurological and mitochondrial dysfunction.
Purpose of the Study:
- To investigate the effects of D-penicillamine-induced copper deficiency on brain mitochondrial enzyme activity in a mouse model.
- To evaluate the potential of this model for studying Menkes' disease and mitochondrial encephalomyopathy.
Main Methods:
- Suckling mice were injected daily with D-penicillamine (1 g/kg/day).
- Evaluated weight gain, physical symptoms, and hindlimb function.
- Measured brain copper content and mitochondrial enzyme activities (cytochrome c oxidase, rotenone-sensitive NADH cytochrome c reductase, succinate cytochrome c reductase) using biochemical and histochemical techniques.
Main Results:
- DP-treated mice exhibited developmental retardation, skin hyperelasticity, edema, and hindlimb paralysis.
- Brain copper levels were significantly reduced (34% of controls).
- Cytochrome c oxidase (complex IV) activity decreased by 51%, while complexes I+III and II+III remained normal. Histochemistry showed reduced staining in Purkinje cells.
Conclusions:
- D-penicillamine-induced copper deficiency selectively impairs brain cytochrome c oxidase activity.
- This mouse model effectively mimics key aspects of Menkes' disease and mitochondrial encephalomyopathy, highlighting mitochondrial dysfunction.
- The findings underscore the critical role of copper in maintaining mitochondrial electron transport chain integrity.
Abstract:
Brain mitochondrial enzyme activities were examined in 15-day-old suckling mice which were daily injected with D-penicillamine (DP), a chelating agent of copper. Newborn mice treated with DP (1 g/kg/day) showed retarded weight gain, hyperelasticity of skin, and a bizarre forelimb posture with subcutaneous edema on experimental day (ED) 7. Paraparesis or dragging of the hindlimbs was observed by ED 15. Brain copper contents of DP-treated mice decreased to 34% of the controls of ED 15. Cytochrome c oxidase activity (complex IV) in the brain showed 51% decrease of the controls, on the contrary, rotenone-sensitive NADH cytochrome c reductase (complex I + III) and succinate cytochrome c reductase (complex II + III) were normal. Histochemistry of cytochrome c oxidase in the cerebellum of DP-treated mice disclosed diffuse reduction of staining, especially in Purkinje cells. These data show that DP-induced copper deficiency in the brain subsequently disturbs mitochondrial electron transport system, selectively cytochrome c oxidase activity. This seems to be a useful animal model not only for Menkes' kinky hair disease but also for mitochondrial encephalomyopathy.