Ammonia Cytotoxicity Involves Mitochondrial Disfunction, Impairment Of Lipid Metabolism And Oxidative Stress.
J.E. O'Connor1, B.F. Kimler, M. Costell, and J. Viña. Dpt. of Biochemistry, University of Valencia, Valencia, Spain; Dpt. of Radiation Biology, Kansas University Medical Center, Kansas City, KS; Instituto de Investigaciones Citológicas, Valencia, Spain
Ammonia is a highly neurotoxic metabolite which may cause cerebral damage and death in clinical conditions due to liver impairment. The biochemical mechanisms of ammonia toxicity are still poorly understood, and several hypotheses have been proposed.
We have applied functional flow cytometry, fluorescence and electron microscopy and biochemical techniques to analyze the effects of ammonia on cultures of Neuro-2a mouse neuroblastoma, L-132 lung fibroblasts and primary cultures of neonatal rat astrocytes, as well as on tissue samples and isolated mitochondria from rats intoxicated acutely or chronically with ammonia.
Our results show that in vitro and in vivo exposure to concentrations of ammonia in the range of human hyperammonemias decrease mitochondrial membrane potential, inhibit fatty acid oxidation and reduce the levels of glutathione. These changes are accompanied by an increased production of oxygen reactive species and by ultrastructural alterations in mitochondria and other cell organelles. These data suggest a role for free radicals in ammonia cytotoxicity, as supported by our results showing a protective effect of carnitine on both lethality and biochemical alterations caused by ammonia.