gamma-Glutamyltranspeptidase-deficient knockout mice as a model to study the relationship between glutathione status, mitochondrial function, and cellular function

gamma-Glutamyltranspeptidase (GGT)-deficient mice (GGT(-/-)) display chroni c glutathione (GSH) deficiency, growth retardation, and die at a young age (<20 weeks). Using livers from these mice. we investigated the relationship between GSH content, especially mitochondrial, and mitochondrial and cellu lar function. We found that the GSH content of isolated liver mitochondria was diminished by greater than or equal to 50% in GGT(-/-) mice when compar ed with wild-type mice. Respiratory control ratios (RCRs) of GGT(-/-) mice liver mitochondria were less than or equal to 60% those of wild-type mice p rimarily as a result of impaired state 3 respiration. Mitochondrial adenine nucleotide content was decreased by greater than or equal to 40% in mitoch ondria obtained from GGT(-/-) mice. We observed a strong correlation betwee n mitochondrial GSH content and RCRs. Even moderate decreases (< 50%) corre lated with adverse effects with respect to respiration. Electron microscopy revealed that livers from GGT(-/-) knockout mice were deprived of fat and glycogen, and swollen mitochondria were observed in animals that were sever ely deprived of GSH. Thus, GGT(-/-) mice exhibit a loss of GSH homeostasis and impaired oxidative phosphorylation, which may be related to the rate of adenosine triphosphate (AIP) formation and subsequently leads to progressi ve liver injury, which characterizes the diseased state. We also found that supplementation of GGT(-/-) mice with N-acetylcysteine (NAC) partially res tored liver GSH, but fully restored mitochondrial GSH and respirator?; func tion. Electron microscopy revealed that the livers of NAG-supplemented GGT( -/-) mice contained fat and glycogen; however, slightly enlarged mitochondr ia were found in some livers. NAC supplementation did not have any benefici al effect on the parameters examined in wildtype mice.