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Mitochondrial bioenergetic impairment has been found in the organelles isolated from rat liver during the prereplicative phase of liver regeneration. To gain insight into the mechanism underlying this impairment, we investigated mitochondrial ultrastructure and membrane permeability properties in the course of liver regeneration after partial hepatectomy, with special interest to the role played by Ca 2+ in this process. The results show that during the first day after partial hepatectomy, significant changes in the ultrastructure of mitochondria in situ occur. Mitochondrial swelling and release from mitochondria of both glutamate dehydrogenase and aspartate aminotransferase isoenzymes with an increase in the mitochondrial Ca 2+ content were also observed. Cyclosporin-A proved to be able to prevent the changes in mitochondrial membrane permeability properties. At 24 h after partial hepatectomy, despite alteration in mitochondrial membrane permeability properties, no release of cytochrome c was found. The ultrastructure of mitochondria, the membrane permeability properties and the Ca 2+ content returned to normal values during the replicative phase of liver regeneration. These results suggest that, during the prereplicative phase of liver regeneration, the changes in mitochondrial ultrastructure observed in liver specimens were correlated with Ca 2+ -induced permeability transition in mitochondria.Keywords: liver regeneration; mitochondria ultrastructure; membrane permeability; calcium; cyclosporin-A.Seventy percent partial hepatectomy (PH) induces cell proliferation until the original mass of the liver is restored [1]. The tissue regeneration process consists of two phases: the prereplicative phase, the duration of which depends on the age of the animal [2,3] as well as on hormones and dietary manipulation [2,4] and the replicative phase, during which a sharp increase in DNA synthesis occurs with active mitosis [2]. In the light of early changes in ATP concentration found in liver after PH, before activation of cell proliferation [5,6], mitochondria were investigated as they are directly involved in the process of liver regeneration [4,[7][8][9][10][11][12][13][14][15][16]. Many mitochondrial functions, including oxidative phosphorylation [11][12][13] and generation of reactive oxygen species [14,15], were investigated in some detail in the prereplicative phase of liver regeneration. In isolated mitochondria, a decrease in the respiratory control index [12], ATP synthesis, probably due to a decrease in the ATPsynthase complex content [14], and glutathione content[13] as well as an increase in malondialdehyde production [14] and oxidant production [15] were found. This suggests the occurrence in the prereplicative phase of liver regeneration of a transient mitochondrial oxidative stress in which mitochondria can also release proteins from the matrix [16]. Despite this, mitochondria recover their functions in the replicative phase of liver regeneration [12,[14][15][16].In this paper, we investigated whether and ho...