A Look into Liver Mitochondrial Dysfunction as a Hallmark in Progression of Brain Energy Crisis and Development of Neurologic Symptoms in Hepatic Encephalopathy

Abstract

Background: The relationship between liver disease and neuropathology in hepatic encephalopathy is well known, but the genesis of encephalopathy in liver failure is yet to be elucidated. Conceptually, the main cause of hepatic encephalopathy is the accumulation of brain ammonia due to impaired liver detoxification function or occurrence of portosystemic shunt. Yet, as well as taking up toxic ammonia, the liver also produces vital metabolites that ensure normal cerebral function. Given this, for insight into how perturbations in the metabolic capacity of the liver may be related to brain pathology, it is crucial to understand the extent of ammonia-related changes in the hepatic metabolism that provides respiratory fuel for the brain, a deficiency of which can give rise to encephalopathy. Methods: Hepatic encephalopathy was induced in starved rats by injection of ammonium acetate. Ammonia-induced toxicity was evaluated by plasma and freeze-clamped liver and brain energy metabolites, and mitochondrial, cytoplasmic, and microsomal gluconeogenic enzymes, including mitochondrial ketogenic enzymes. Parameters of oxidative phosphorylation were recorded polarographically with a Clark-type electrode, while other measures were determined with standard fluorometric enzymatic methods. Results: Progressive impairment of liver mitochondrial respiration in the initial stage of ammonia-induced hepatotoxicity and the subsequent energy crisis due to decreased ATP synthesis lead to cessation of gluconeogenesis and ketogenesis. Reduction in glucose and ketone body supply to the brain is a terminal event in liver toxicity, preceding the development of coma. Conclusions: Our study provides a framework to further explore the relationship between hepatic dysfunction and progression of brain energy crisis in hepatic encephalopathy.

Is NMDA-Receptor-Mediated Oxidative Stress in Mitochondria of Peripheral Tissues the Essential Factor in the Pathogenesis of Hepatic Encephalopathy?

“…Considering the fact that effects of MK-801 on the rate of H 2 O 2 formation in liver and pancreas mitochondria were similar to those implicated in the brain mitochondria of hyperammonemic animals [51], we can assume that, in addition to the numerous known factors that inhibit the production of H 2 O 2 in mitochondria [97], the ammonia-related reduction in H 2 O 2 production in liver and pancreas mitochondria could be due to a decrease in NADH availability [69,70], as evident from a significant increase in the mitochondrial NAD/NADH ratio [10,56], as well as due to a significant decrease in hepatic (Figure 4) and pancreatic (Figure 6) activities of Mn 2+ -SOD localized in the mitochondrial matrix.…”

“…Isolation of Mitochondria Using a Self-Generated Percoll Gradient Pancreas, heart, and liver mitochondria were isolated by a combination of differential and self-generated Percoll-gradient centrifugation, essentially according to a protocol developed by Graham [55] except that 5 µM aprotinin, an inhibitor from a range of serine proteases, was added to isolation medium. This protocol enables a highly purified and intact preparation, as assessed by relatively low contamination of the mitochondria with other subcellular compartments (low marker enzyme activities), sufficiently high respiratory control index, and close to theoretical ADP/O ratios (phosphorylation capacity) upon oxidation of lipid and non-lipid substrates [56]. Mitochondrial protein concentration was determined by the Lowry method using bovine serum albumin as standard [57].…”

Severe Acute Liver Dysfunction Induces Delayed Hepatocyte Swelling and Cytoplasmic Vacuolization, and Delayed Cortical Neuronal Cell Death

“…Several methods have been devised to study HE. Based on previous reports using ammonium acetate [ 24 , 25 , 26 , 27 , 28 ], a simple and accurate animal model was devised to exhibit elevated blood ammonia levels. Our mouse model was used to pathologically investigate how elevated blood ammonia levels affect the brain.…”

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

“…Ammonia-induced toxicity in starved rats led to an energy crisis due to decreased ATP synthesis and cessation of gluconeogenesis and ketogenesis. Reduction in glucose and ketone body supply to the brain was a terminal event in liver toxicity, preceding the development of coma [ 80 ]. Such studies could provide a framework to further explore the relationship between hepatic dysfunction and progression of a brain energy crisis.…”