An array of mitochondrial alterations in the hepatocytes of long-evans cinnamon rats

Abstract

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.

Loss of the Intermembrane Space Protein Mgm1/OPA1 Induces Swelling and Localized Constrictions along the Lengths of Mitochondria

“…The cristae in some cells were reoriented such that they ran parallel to the longitudinal axis of the mitochondria, whereas in other cells the cristae were reticular. Similar longitudinal and reticular cristae were reported previously for various other pathological conditions, for example in patients treated with chloramphenicol (36), patients with mitochondrial encephalomyopathy (37), rats treated with a hypocholesterolemic agent (38), and in certain mutant mice (39). Besides longitudinal and reticular cristae, we also observed mitochondria with swollen cristae and a condensed matrix.…”

Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease

“…Mitochondria from Atp7b -/-hepatocytes displayed rounded cristae and enlarged intermembrane spaces with membranous relics (Figure 2, B-D, and Supplemental Figure 2), as previously described in WD patients and Atp7b -/-rats (23)(24)(25)28). We classified these mitochondrial alterations into 3 categories: normal (Figure 2A), altered (mitochondria with detectable enlargements in cristae and/or intermembrane spaces; Figure 2, B and C), and severely condensed (mitochondria with massive matrix condensation, enlargement of cristae and intermembrane spaces, and shape deterioration; Figure 2D).…”

“…Sternlieb, for instance, failed to observe any correlation between the type/extent of mitochondrial abnormality and the hepatic copper concentration, be it in WD patients or in Atp7b -/-LEC rats (24,28). Sokol and coworkers, however, reported that excessive copper feeding does cause structural and functional deficits in rat liver mitochondria (9,29).…”

L‐carnitine inhibits hepatocarcinogenesis via protection of mitochondria

“…16 -18 Furthermore, the severity of ultrastructural alterations in the mitochondria correlated with the degree of icterus displayed by the rats. 17 The amounts of endogenously produced free radicals were markedly increased in cells with mutant mtDNA and dysfunctional mitochondria. 9,10 As a result, mitochondria would enter a vicious circle in which the secondary oxidative modification of mitochondria itself is further amplified by increased production of free radicals.…”

“…The striking ultrastructural and functional abnormal alterations in mitochondria are also observed in the hepatocytes of LEC rats. 16 -18 Furthermore, the severity of ultrastructural alterations in mitochondria correlates with the degree of icterus displayed by the rats, 17 suggesting that hepatic mitochondria are important targets in copper-induced toxicity in LEC rats. Therefore, in this study, we used LEC rats to investigate the role of mitochondria in the process of hepatocarcinogenesis.…”