Mitochondrial respiratory function and antioxidant capacity in normal and cirrhotic livers following partial hepatectomy

Abstract

For many liver malignancies, major hepatectomy is the usual therapy. Although a normal liver has a tremendous capacity for regeneration, liver hepatectomy in humans is usually carried out on a diseased liver and, in such cases, liver regeneration takes place in a cirrhotic remnant. Mitochondrial function in cirrhotic livers shows a variety of changes compared to control livers. This study investigated how mitochondrial respiratory function and antioxidant capacity change following partial hepatectomy of cirrhotic livers, because liver regeneration requires greater energy demands and control of oxidative stress. Cirrhosis was induced in male Wistar-Furth rats by administration of thioacetamide. NADH-cytochrome c reductase activity, mitochondrial glutathione peroxidase activity and mitochondrial GSH levels were all significantly lowered in cirrhotic livers and in the cirrhotic remnants up to 72 h after 70% hepatectomy when compared to the corresponding controls. Lower respiratory control ratios with succinate as substrate were also observed from 6 to 48 h post-hepatectomy. At 24 h post-hepatectomy, higher levels of lipid peroxidation were observed. We conclude that, compared to the controls, cirrhotic livers have diminished oxidative phosphorylation capabilities due to changes in NADH and FADH(2)-linked respiration as well as impaired antioxidant defenses following partial hepatectomy. Both of these factors, if critical, could then impede liver regeneration.

Does Simple Steatosis Affect Liver Regeneration after Partial Hepatectomy in Rats?

“…However, oxygen consumption at state 3 in the presence of complex I substrates showed a trend of transient increasing respiration 24 and 48 hours after PHx in both lean and steatotic groups. Such increase in respiration at state 3 after PHx was not detected when complex II substrate was used which corresponds with findings of Yang (56). We also observed a trend of transient increase in RCI at presence of complex II substrate in both groups 24 h after PHx which is in accordance with literature (56).…”

Expression patterns of cytokine, growth factor and cell cycle-related genes after partial hepatectomy in rats with thioacetamide-induced cirrhosis

“…It addition, liver regeneration is also critically dependent on ATP stores and the reduction in liver proliferation in cirrhotic livers may be due in part to inadequate mitochondrial respiratory function. Cirrhotic livers indeed have reduced complex I activity and lower respiratory control ratios following PH as shown by us and others [13,50,51] .…”

“…The induction of cirrhosis, partial hepatectomy (PH) and harvesting of the livers has been previously described [13,14] . In brief, cirrhosis was induced in ten-week-old male Wistar-Furth rats by intraperitoneal injection of 300 mg thioacetamide/kg thrice weekly for 10 wk.…”

Additive Effects of Mitochondrion-targeted Cytochrome CYP2E1 and Alcohol Toxicity on Cytochrome c Oxidase Function and Stability of Respirosome Complexes

“…Some studies suggest that complex I and complex II are altered in hepatocytes in various liver pathologies (15,16), whereas the others consider complex II to be the most resistant complex, which is not damaged even in liver cirrhosis (3,4,(17)(18)(19). Cytochrome c oxidase (CcO) is the terminal oxidase of the electron transport chain and contains three large catalytic subunits (I, II, and III) encoded in the mitochondrial genome and up to 10 smaller subunits encoded in the nuclear genome.…”