Ammonia-induced mitochondrial impairment is intensified by manganese co-exposure: relevance to the management of subclinical hepatic encephalopathy and cirrhosis-associated brain injury

Aim of the study Hepatic encephalopathy (HE) is a neuropsychiatric syndrome ensuing from liver failure. The liver is the major site of ammonia detoxification in the human body. Hence, acute and chronic liver dysfunction can lead to hyperammonemia. Manganese (Mn) is a trace element incorporated in several physiological processes in the human body. Mn is excreted through bile. It has been found that cirrhosis is associated with hyperammonemia as well as body Mn accumulation. The brain is the primary target organ for both ammonia and Mn toxicity. On the other hand, brain mitochondria impairment is involved in the mechanism of Mn and ammonia neurotoxicity. Material and methods The current study was designed to evaluate the effect of Mn and ammonia and their combination on mitochondrial indices of functionality in isolated brain mitochondria. Isolated brain mitochondria were exposed to increasing concentrations of ammonia and Mn alone and/or in combination and several mitochondrial indices were assessed. Results The collapse of mitochondrial membrane potential, increased mitochondrial permeabilization, reactive oxygen species formation, and a significant decrease in mitochondrial dehydrogenase activity and ATP content were evident in Mn-exposed (0.005-1 mM) brain mitochondria. On the other hand, ammonia (0.005-0.5 mM) caused no significant changes in brain mitochondrial function. It was found that co-exposure of the brain mitochondria to Mn and ammonia causes more evident mitochondrial impairment in comparison with Mn and/or ammonia alone. Conclusions These data indicate additive toxicity of ammonia and Mn in isolated brain mitochondria exposed to these neurotoxins.

• Publication year

  2019

• Venue

  Clinical and Experimental Hepatology

• Publication date

  2019-05-01

• Fields of study

  Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.5114/ceh.2019.85071PMID 31501786PMCID 6728860
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• MDSC; the Most Important Cell You Have Never Heard Of.

  2019cited by this paper
• Regulation of mitochondrial function and energy metabolism: A primary mechanism of cytoprotection provided by carnosine

  2018cited by this paper
• The Effects of Cimetidine, N-Acetylcysteine, and Taurine on Thioridazine Metabolic Activation and Induction of Oxidative Stress in Isolated Rat Hepatocytes

  2018cited by this paper
• Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury.

  2018cited by this paper
• Taurine treatment preserves brain and liver mitochondrial function in a rat model of fulminant hepatic failure and hyperammonemia.

  2017cited by this paper
• Manganese and Mitochondrial Function

  2017cited by this paper
• Carnosine ameliorates liver fibrosis and hyperammonemia in cirrhotic rats.

  2017cited by this paper
• Taurine Alleviates Brain Tissue Markers of Oxidative Stress in a Rat Model of Hepatic Encephalopathy

  2017cited by this paper
• Carnosine protects brain mitochondria under hyperammonemic conditions: Relevance to hepatic encephalopathy treatment

  2017cited by this paper
• Carnosine Supplementation Mitigates Brain Tissue Markers of Oxidative Stress in a Rat Model of Fulminant Hepatic Failure

  2017cited by this paper
• Paradoxical effect of methimazole on liver mitochondria: In vitro and in vivo.

  2016cited by this paper
• In vitro/vivo studies towards mechanisms of risperidone-induced oxidative stress and the protective role of coenzyme Q10 and N-acetylcysteine

  2016cited by this paper
• Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction.

  2016cited by this paper
• Neurotoxicity of Ammonia

  2016cited by this paper
• Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals

  2016cited by this paper
• Cirrhotic patients have good insight into their daily functional impairment despite prior hepatic encephalopathy: comparison with PROMIS norms

  2016cited by this paper
• “Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

  2016influential reference
• In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity

  2016cited by this paper
• Identifying Compounds that Induce Opening of the Mitochondrial Permeability Transition Pore in Isolated Rat Liver Mitochondria

  2014cited by this paper
• Ammonia-induced energy disorders interfere with bilirubin metabolism in hepatocytes.

  2014cited by this paper
• From the liver to the brain: manganese matters

  2014influential reference
• Role of astrocytes in manganese mediated neurotoxicity

  2013influential reference
• Hepatic encephalopathy: effects of liver failure on brain function

  2013cited by this paper
• Manganese and the brain.

  2013cited by this paper
• A simple method for isolating rat brain mitochondria with high metabolic activity: effects of EDTA and EGTA.

  2013cited by this paper
• Ammonia toxicity to the brain

  2013cited by this paper
• Effect of garlic-derived organosulfur compounds on mitochondrial function and integrity in isolated mouse liver mitochondria.

  2012influential reference
• The Role of Mitochondrial Oxidative Stress and ATP Depletion in the Pathology of Manganese Toxicity

  2012cited by this paper
• Manganese accumulation in the CNS and associated pathologies

  2011influential reference
• Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy

  2010influential reference
• Minimal hepatic encephalopathy: Consensus statement of a working party of the Indian National Association for Study of the Liver

  2010cited by this paper
• Oxidative damage and neurodegeneration in manganese-induced neurotoxicity.

  2009cited by this paper
• Signaling factors in the mechanism of ammonia neurotoxicity

  2009cited by this paper
• Identifying the direct effects of ammonia on the brain

  2009influential reference
• In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain.

  2008influential reference
• Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures.

  2008cited by this paper
• Cerebral Glutamine and Glutamate Levels in Relation to Compromised Energy Metabolism: A Microdialysis Study in Subarachnoid Hemorrhage Patients

  2007cited by this paper
• Follow-up of patients affected by manganese-induced Parkinsonism after treatment with CaNa2EDTA.

  2006cited by this paper
• Luminescent Determination of ATP Concentrations Using the Clarity™ Luminescence Microplate Reader

  2006cited by this paper
• Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis.

  2005cited by this paper
• Nutritional aspects of manganese homeostasis.

  2005cited by this paper
• Basal Ganglia Accumulation and Motor Assessment Following Manganese Chloride Exposure in the C57BL/6 Mouse

  2005cited by this paper
• The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation

  2005cited by this paper
• Manganese Neurotoxicity

  2004cited by this paper
• Ammonia Neurotoxicity and the Mitochondrial Permeability Transition

  2004cited by this paper
• Oxidative Stress in the Pathogenesis of Hepatic Encephalopathy

  2004cited by this paper
• Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels

  2004cited by this paper
• Ammonia Neurotoxicity: Role of the Mitochondrial Permeability Transition

  2003cited by this paper
• Oxidative and nitrosative stress in ammonia neurotoxicity

  2003influential reference
• Oxidative stress involves in astrocytic alterations induced by manganese.

  2002cited by this paper
• Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver

  2002cited by this paper
• Neurobiology of ammonia.

  2002cited by this paper
• Mitochondrial dysfunction in acute hyperammonemia.

  2002cited by this paper
• Striatal manganese accumulation induces changes in dopamine metabolism in the cirrhotic rat.

  2001influential reference
• Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes

  2001cited by this paper
• Manganese neurotoxicity: a mechanistic hypothesis.

  1999cited by this paper
• Manganese and calcium transport in mitochondria: implications for manganese toxicity.

  1999cited by this paper
• Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome.

  1999cited by this paper
• Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction.

  1999influential reference
• Subclinical hepatic encephalopathy impairs daily functioning

  1998influential reference
• High prevalence of sleep disturbance in cirrhosis

  1998cited by this paper
• The diagnosis of subclinical hepatic encephalopathy in patients with cirrhosis using neuropsychological tests and automated electroencephalogram analysis

  1996influential reference
• Manganese and chronic hepatic encephalopathy.

  1995influential reference
• Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy

  1995cited by this paper
• Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation.

  1992cited by this paper
• Neurotoxicity of ammonia and fatty acids: Differential inhibition of mitochondrial dehydrogenases by ammonia and fatty acyl coenzyme a derivatives

  1991cited by this paper
• Protective effect of L‐carnitine on hyperammonemia

  1984cited by this paper
• Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.

  1983cited by this paper
• A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.

  1976cited by this paper

• Altered hepatic metabolism in Down syndrome.

  2026cites this paper
• Decoding TGR5: A Comprehensive Review of Its Impact on Cerebral Diseases.

  2025cites this paper
• Altered Hepatic Metabolism in Down Syndrome

  2025cites this paper
• Mitigatory antioxidant effect of Lycopene against the polystyrene microplastics-induced neurotoxicity via modulation of mTOR/Beclin-1 activities in adult male Wistar rats

  2024cites this paper
• Hepatic encephalopathy complications are diminished by piracetam via the interaction between mitochondrial function, oxidative stress, inflammatory response, and locomotor activity

  2023cites this paper
• Green synthesized cerium oxide nanoparticles ameliorate hepatic and cognitive dysfunctions in thioacetamide-induced hepatic encephalopathy in rats: Modulation of TLR-4/NF-κB/Caspase-3 signaling pathways

  2023cites this paper
• Mitochondrial Impairment and Oxidative Stress Are Essential Mechanisms Involved in the Pathogenesis of Acute Kidney Injury

  2023cites this paper
• Pulmonary inflammation, oxidative stress, and fibrosis in a mouse model of cholestasis: the potential protective properties of the dipeptide carnosine

  2023cites this paper
• Low‐dose ketamine improves animals' locomotor activity and decreases brain oxidative stress and inflammation in ammonia‐induced neurotoxicity

  2023cites this paper
• Pre/postnatal taurine supplementation improves neurodevelopment and brain function in mice offspring: A persistent developmental study from puberty to maturity.

  2023cites this paper
• Dextromethorphan improves locomotor activity and decreases brain oxidative stress and inflammation in an animal model of acute liver failure

  2022cites this paper
• A review of basic to clinical studies of the association between hyperammonemia, methamphetamine

  2022cites this paper
• Methylene blue and photobiomodulation recover cognitive impairment in hepatic encephalopathy through different effects on cytochrome c-oxidase.

  2021cites this paper
• Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury

  2021cites this paper
• A histopathological evaluation on the effect of captopril in cyclophosphamide-induced hemorrhagic cystitis

  2021cites this paper
• Drug‐induced organ injury in coronavirus disease 2019 pharmacotherapy: Mechanisms and challenges in differential diagnosis and potential protective strategies

  2021cites this paper
• The Role of Mitochondrial Impairment and Oxidative Stress in the Pathogenesis of Lithium-Induced Reproductive Toxicity in Male Mice

  2021cites this paper
• N-acetyl cysteine treatment preserves mitochondrial indices of functionality in the brain of hyperammonemic mice

  2020cites this paper
• The Potential Neuroprotective Role of Citicoline in Hepatic Encephalopathy

  2020cites this paper
• Skeletal Muscle Mitochondrial Impairment in Cirrhosis-Induced Sarcopenia

  2020cites this paper
• Taurine and isolated mitochondria: A concentration-response study

  2019cites this paper