Changes in ultrastructure and the occurrence of permeability transition in mitochondria during rat liver regeneration

Abstract

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...

Changes in Mitochondrial Adenine Nucleotides and in Permeability Transition in Two Models of Rat Liver Regeneration

“…Although MPT can constitute a critical step of the apoptotic cascade, it has been found recently that this event would occur in the absence of reliable apoptosis during the prereplicative stage of LR. 6 Acute CCl 4 administration to rats constitutes another experimental model for inducing LR, which is remarkably similar (with some important differences) to that found after PH. 11 Here, the participation of mitochondrial oxidative function in the compensatory liver growth is completely unknown.…”

“…6 Despite these dramatic changes on mitochondrial ultrastructure and membrane permeability properties, apoptotic events did not proceed in the PHinduced regenerating liver. 6 Such alterations in mitochondrial membrane integrity have been related to growth factors or cytokine-induced mitochondrial oxidant production after PH. 25 However, we did not find an initial PH-induced onset of MPT, but rather this phenomenon occurred later in a lower magnitude.…”

“…5 Indeed, it has been reported very recently that changes in mitochondrial ultrastructure during the prereplicative phase of LR correlate with calcium-induced permeability transition in mitochondria. 6 Alterations in the membrane permeabilization, event known as mitochondrial permeability transition (MPT), regulate maintenance of the electrical potential in mitochondrial membranes. 7 The MPT results in the rapid efflux of glutathione and calcium, large-amplitude swelling, and a collapsed ⌬.…”

Probing Prometheus: Fat Fueling the Fire?

“…22 Further, there appears to be mitochondrial bioenergetic impairment during the prereplicative phase of liver regeneration, a change which has been attributed to Ca 2ϩ Ϫinduced permeability transition. 23 Compensatory pathways for generation of intracellular energy sources may need to be upregulated to account for such changes.…”

Inhibitory Effect of Vitamin E Administration on the Progression of Liver Regeneration Induced by Partial Hepatectomy in Rats

“…Indeed, increased LP has been found in liver homogenates from regenerating liver (Lambotte et al, 1989;Ueda et al, 1983), despite the fact that necrotic or apoptotic hepatocytes have not been observed at the onset of the proliferating liver (Oikawa and Novikoff, 1995). In addition, no changes in events characterizing the onset of mitochondrial permeability transition have been noticed in the regenerating liver (Guerrieri et al, 2002), and mitochondrial oxidative and phosphorylative activities are largely increased in PH rats (Hernández-Muñoz et al, 2003).…”