Mitochondrial adaptations to steatohepatitis induced by a methionine- and choline-deficient diet

Abstract

There is accumulating evidence that mitochondria play a key role in NAFLD. Nevertheless, the mitochondrial consequences of steatohepatitis are still unknown. The bioenergetic changes induced in a methionine-and choline-deficient diet (MCDD) model of steatohepatitis were studied in rats. Liver mitochondria from MCDD rats exhibited a higher rate of oxidative phosphorylation with various substrates, a rise in cytochrome oxidase (COX) activity, and an increased content in cytochrome aa 3. This higher oxidative activity was associated with a low efficiency of the oxidative phosphorylation (ATP/O, i.e., number of ATP synthesized/ natom O consumed). Addition of a low concentration of cyanide, a specific COX inhibitor, restored the efficiency of mitochondria from MCDD rats back to the control level. Furthermore, the relation between respiratory rate and protonmotive force (in the nonphosphorylating state) was shifted to the left in mitochondria from MCDD rats, with or without cyanide. These results indicated that, in MCDD rats, mitochondrial ATP synthesis efficiency was decreased in relation to both proton pump slipping at the COX level and increased proton leak although the relative contribution of each phenomenon could not be discriminated. MCDD mitochondria also showed a low reactive oxygen species production and a high lipid oxidation potential. We conclude that, in MCDD-fed rats, liver mitochondria exhibit an energy wastage that may contribute to limit steatosis and oxidative stress in this model of steatohepatitis.

Time course of liver mitochondrial function and intrinsic changes in oxidative phosphorylation in a rat model of sepsis

“…In particular, cytochrome c oxidase activity and/or stoichiometry are believed to control and adjust oxidative phosphorylation in stress conditions [20, 21, 34]. Indeed, several studies provide evidence that when the activity and content of cytochrome c oxidase decrease (redox slip) [34] or increase [35, 36], the mitochondrial efficiency (ATP/O) moves in the opposite way. The present study shows that sepsis decreased the content and activity of cytochrome c oxidase, in line with previous studies [33, 37–39].…”

“…These results suggest that cytochrome c oxidase might be responsible for the higher mitochondrial ROS generation observed in the septic shock groups. Indeed, partial suppression of cytochrome c oxidase activity induces an increase in ROS generation [18], whereas an increased activity of this mitochondrial enzyme results in decreased ROS production at the level of mitochondria [36]. As a rational consequence, the artificial increase in cytochrome c oxidase activity by cytochrome c infusion has been reported to restore mitochondrial oxygen consumption [49, 50] and decrease ROS generation.…”

5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) Effect on Glucose Production, but Not Energy Metabolism, Is Independent of Hepatic AMPK in Vivo

“…Mitochondria Isolation and Oxygen Consumption-Mitochondrial isolation was performed using standard homogenization and differential centrifugation methods as previously described (28). Briefly, liver tissue was weighed and subsequently minced in 5 ml of ice-cold mitochondrial extraction buffer containing 250 mM sucrose, 2 mM KH 2 PO 4 , 1 mM EGTA, and 20 mM Tris⅐HCl (pH 7.2).…”

Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease

“…UCP-2-dependent mitochondrial uncoupling can be perceived as a protective mechanism to halt damage progression but compromises on the other hand the liver capacity to respond to acute high-energy demands, such as ischaemia-reperfusion injury. Additional abnormalities of hepatic energy metabolism that have been reported in human and animal NASH (rat models of high fat, methionine and choline-deficient diet) include increased ROS production, abnormal cellular and mitochondrial redox homeostasis, oxidative stress-mediated depletions of mitochondrial DNA encoding some of the polypeptide components of mitochondrial respiratory chain and increased rate of b-oxidation (Miele et al, 2003;Morris et al, 2011;Serviddio et al, 2008a;Romestaing et al, 2008) (Table 1).…”