Neurochemistry International 40 (2002) 487–491 Mitochondrial dysfunction in acute hyperammonemia Vicente Felipo a , Roger F. Butterworth b,* a Instituto Investigaciones Citologicas de la Fundacion Valenciana de Investigaciones Biomedicas, Valencia, Spain b Neuroscience Research Unit, Hôpital Saint-Luc CHUM, University of Montreal, 1058 St-Denis Street, Montreal, Que., Canada H2X 3J4 Accepted 30 October 2001 Abstract Acute hyperammonemia resulting from congenital urea cycle disorders, Reye syndrome or acute liver failure results in severe neuronal dysfunction, seizures and death. Increasing evidence suggests that acute hyperammonemia results in alterations of mitochondrial and cellular energy function resulting from ammonia-induced inhibition of the tricarboxylic acid cycle enzyme -ketoglutarate dehydrogenase and by activation of the NMDA receptor. Antagonists of this receptor and NOS inhibitors prevent acute ammonia-induced seizures and mortality and prevent acute ammonia-induced changes in mitochondrial calcium homeostasis and cellular energy metabolism. Acute hyperammonemia also results in decreased activities of free radical scavenging enzymes and again, free radical formation due to ammonia exposure is prevented by either NMDA receptor antagonists or NOS inhibitors. Acute hyperammonemia also results in activation of “peripheral-type” benzodiazepine receptors and monoamine oxidase-B, enzymes which are localized on the mitochondrial membranes of astrocytes in the CNS. Activation of these receptors results in mitochondrial swelling and in increased degradation of monoamines, respectively. Alterations of mitochondrial function could contribute to the neuronal dysfunction characteristic of acute hyperammonemic syndromes. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Hyperammonemia; Ammonia; Mitochondrial dysfunction; NMDA receptor activation; Nitric oxide synthase; Peripheral-type benzodiazepine receptors; Reactive oxygen species; Urea cycle enzymopathies; Acute liver failure 1. Introduction Acute hyperammonemia is associated with congenital urea cycle disorders, Reye syndrome and acute (or fulmi- nant) hepatic failure. Symptoms in these disorders include seizures and coma. In infants with urea cycle enzymopathies, mental retardation and cerebral palsy may result (Msall et al., 1984; Michalak and Butterworth, 1997). Acute exposure of brain preparations to pathophysiolo- gically relevant concentrations of ammonia has numer- ous metabolic and neurophysiologic effects. Such effects include alterations of synaptic inhibition and excitation (Szerb and Butterworth, 1992), effects on cerebral energy metabolism and modifications of neurotransmitter-related processes. An increasing body of evidence suggests that acute exposure of brain to ammonia results in alterations of mitochondrial function. Furthermore, neuropathological evaluation of brain tissue from humans and experimental animals with congenital hyperammonemias reveal evidence of NMDA receptor-mediated excitotoxicity (Robinson et al., * Corresponding author. Tel.: +1-514-890-8310x35759; fax: +1-514-412-7314. E-mail address: butterwr@medclin.umontreal.ca (R.F. Butterworth). 1995). This article reviews evidence that mitochondrial dysfunction occurs in acute hyperammonemia and that mi- tochondrial dysfunction is implicated in the pathogenesis of neuronal dysfunction and cell loss in this condition. 1.1. Neuropathology of acute hyperammonemia The nature and extent of neuropathologic damage resul- ting from acute exposure of brain to increased concentra- tions of ammonia depends upon the severity and duration of the exposure and the age of the animal or human patient subjected to the exposure. In mature brain, acute hyperam- monemia resulting from, for example, acute liver failure, results in cytotoxic brain edema characterized by swelling of astrocytes. Such cell swelling if sufficiently severe may lead to increased intracranial pressure and brain herniation. Brain herniation is the major cause of death in acute liver failure in adults and its presence is correlated with arterial ammonia concentrations (Clemmensen et al., 1999). Exposure of immature brain to ammonia, on the other hand, results not only in brain edema but also in severe neu- ronal cell loss. For example, neuropathologic examination of brain tissue from patients with acute hyperammonemia resulting from congenital deficiencies of the urea cycle 0197-0186/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0197-0186(01)00119-X