Thioltransferase (glutaredoxin) mediates recovery of motor neurons from excitotoxic mitochondrial injury.
Mitochondrial dysfunction involving electron transport components is implicated in the pathogenesis of several neurodegenerative disorders and is a critical event in excitotoxicity. Excitatory amino acid L-beta-N-oxalylamino-L-alanine (L-BOAA), causes progressive corticospinal neurodegeneration in humans. In mice, L-BOAA triggers glutathione loss and protein thiol oxidation that disrupts mitochondrial complex I selectively in motor cortex and lumbosacral cord, the regions affected in humans. We examined the factors regulating postinjury recovery of complex I in CNS regions after a single dose of L-BOAA. The expression of thioltransferase (glutaredoxin), a protein disulfide oxidoreductase regulated through AP1 transcription factor was upregulated within 30 min of L-BOAA administration, providing the first evidence for functional regulation of thioltransferase during restoration of mitochondrial function. Regeneration of complex I activity in motor cortex was concurrent with increase in thioltransferase protein and activity, 1 hr after the excitotoxic insult. Pretreatment with alpha-lipoic acid, a thiol delivery agent that protects motor neurons from L-BOAA-mediated toxicity prevented the upregulation of thioltransferase and AP1 activation, presumably by maintaining thiol homeostasis. Downregulation of thioltransferase using antisense oligonucleotides prevented the recovery of complex I in motor cortex and exacerbated the mitochondrial dysfunction in lumbosacral cord, providing support for the critical role for thioltransferase in maintenance of mitochondrial function in the CNS.
D000818:Animals; D042967:Electron Transport Complex I; D054477:Glutaredoxins; D008161:Lumbosacral Region; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009044:Motor Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011490:Protein Disulfide Reductase (Glutathione); D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D054477:Glutaredoxins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D008063:Thioctic Acid; D010088:Oxidoreductases; D009247:NADH, NADPH Oxidoreductases; D011490:Protein Disulfide Reductase (Glutathione); D042967:Electron Transport Complex I