Thioltransferase (glutaredoxin) mediates recovery of motor neurons from excitotoxic mitochondrial injury

Rajappa S. Kenchappa, Latha Diwakar, Michael R. Boyd, Vijayalakshmi Ravindranath

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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-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 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 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.

Original languageEnglish (US)
Pages (from-to)8402-8410
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2002

Keywords

  • Brain
  • Complex I
  • Excitatory amino acid
  • Glutaredoxin
  • Glutathione
  • Mitochondria
  • Motor neuron disease
  • Oxidative stress

ASJC Scopus subject areas

  • Neuroscience(all)

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