An array of mitochondrial alterations in the hepatocytes of Long-Evans Cinnamon rats

In an attempt to identify the cellular targets of copper toxicity, we studied the ultrastructure of hepatocytes in the livers of 23 Long-Evans Cinnamon (LEC) rats ranging in age from 10 to 89 weeks. The hepatic copper concentration ranged from 325 to 2,126 (mean, 930) micrograms/g dry weight. Thirteen rats displayed varying degrees of jaundice at the time of killing. Numerous nuclei were indented by cytoplasmic invaginations. Conspicuous abnormalities were displayed by mitochondria. These included marked pleomorphism; increased or diminished matrical density; rearrangement, elongation, dilatation, stacking, or disappearance of cristae; absence of matrical granules; presence of matrical inclusions of flocculent electron-dense deposits; and degenerative changes. The severity of the ultrastructural changes did not correlate with the hepatic copper concentration but did correlate with the degree of the icterus displayed by the rats. Certain mitochondrial changes resembled those encountered in the hepatocytes of patients with Wilson's disease, confirming that these organelles are important targets of copper toxicity.