Thiol oxidation and loss of mitochondrial complex I precede excitatory amino acid-mediated neurodegeneration

Human ingestion of "chickling peas" from the plant Lathyrus sativus, which contains an excitatory amino acid, L-BOAA (L-beta-N-oxalylamino-L-alanine), leads to a progressive corticospinal neurodegenerative disorder, neurolath yrism. Exposure to L-BOAA, but not its optical enantiomer D-BOAA, causes mi tochondrial dysfunction as evidenced by loss of complex I activity in vitro in male mouse brain slices and in vivo in selected regions of mouse CNS (l umbosacral cord and motor cortex). Loss of complex I activity in lumbosacra l cord after L-BOAA administration to mice was accompanied by concurrent lo ss of glutathione. The inhibited complex I activity in mitochondria isolate d from lumbosacral cord of animals treated with L-BOAA rebounded after incu bation with the thiol-reducing agent dithiothreitol, indicating that oxidat ion of protein thiols to disulfides was responsible for enzyme inhibition. The inhibition of complex I could be abolished by pretreatment with antioxi dant thiols such as glutathione ester and a-lipoic acid. Chronic treatment of male mice, but not female mice, with L-BOAA resulted in loss of complex I activity and vacuolation and dendritic swelling of neurons in the motor c ortex and lumbar cord, paralleling the regionality of the aforementioned bi ochemical effects on CNS mitochondria. These results support the view that thiol oxidation and concomitant mitochondrial dysfunction (also implicated in other neurodegenerative disorders), occurring downstream of glutamate re ceptor activation by L-BOAA, are primary events leading to neurodegeneratio n. Maintenance of protein thiol homeostasis by thiol delivery agents could potentially offer protection against excitotoxic insults such as those seen with L-BOAA.