RT Journal Article
SR Electronic
T1 Thioltransferase (Glutaredoxin) Mediates Recovery of Motor Neurons from Excitotoxic Mitochondrial Injury
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8402
OP 8410
DO 10.1523/JNEUROSCI.22-19-08402.2002
VO 22
IS 19
A1 Rajappa S. Kenchappa
A1 Latha Diwakar
A1 Michael R. Boyd
A1 Vijayalakshmi Ravindranath
YR 2002
UL http://www.jneurosci.org/content/22/19/8402.abstract
AB Mitochondrial dysfunction involving electron transport components is implicated in the pathogenesis of several neurodegenerative disorders and is a critical event in excitotoxicity. Excitatory amino acidl-β-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 ofl-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 α-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.