Ammonia neurotoxicity: role of the mitochondrial permeability transition.
Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with severe liver disease. Although the mechanisms responsible for HE remain elusive, ammonia is generally considered to be involved in its pathogenesis, and astrocytes are thought to be the principal target of ammonia neurotoxicity. Altered bioenergetics and oxidative stress are also thought to play a major role in this disorder. In this paper, we present data invoking the mitochondrial permeability transition (MPT) as a factor in the pathogenesis of HE/hyperammonemia. The MPT is a Ca2+-dependent, cyclosporin A (CsA) sensitive process due to the opening of a pore in the inner mitochondrial membrane that leads to a collapse of ionic gradients and ultimately to mitochondrial dysfunction. Many of the factors that facilitate the induction of the MPT are also known to be implicated in the mechanism of HE, including free radicals, Ca2+, nitric oxide, alkaline pH, and glutamine. We have recently shown that treatment of cultured astrocytes with 5 mM NH4Cl resulted in a dissipation of the mitochondrial membrane potential (delta(psi)m), which was sensitive to CsA. Similarly treated cultured neurons failed to show a loss of the delta(psi)m. Further support for the ammonia induction of the MPT was obtained by observing an increase in mitochondrial permeability to 2-deoxyglucose-6-phosphate, and a decrease in calcein fluorescence in astrocytes after ammonia treatment, both of which were also blocked by CsA. CsA was likewise capable of exerting a protective effect against hyperammonemia in mice. Taken together, our data suggest that the MPT represents an important component of the pathogenesis of HE and other hyperammonemic states.
Rama Rao
K V
KV
Department of Pathology, University of Miami School of Medicine, Miami, Florida 33101, USA.
Jayakumar
A R
AR
Norenberg
D M
DM
D000641:Ammonia / Q000506:poisoning* / Q000633:toxicity; D000818:Animals; D004734:Energy Metabolism; D006801:Humans; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010539:Permeability / Q000187:drug effects
D000641:Ammonia