Neurotoxicity Research

, Volume 14, Issue 4, pp 367–382 | Cite as

Unregulated mitochondrial GSK3β activity results in NADH:Ubiquinone oxidoreductase deficiency

  • Taj D. King
  • Buffie Clodfelder-Miller
  • Keri A. Barksdale
  • Gautam N. Bijur


GSK3β is prominent for its role in apoptosis signaling and has been shown to be involved in Parkinson’s disease (PD) pathogenesis. The overall effects of GSK3β activity on cell fate are well-established, but the effects of mitochondrial GSK3β activity on mitochondrial function and cell fate are unknown. Here we selectively expressed constitutively active GSK3β within the mitochondria and found that this enhanced the apoptosis signaling activated by the PD-mimetic NADH:ubiquinone oxidoreductase (complex I) inhibitors 1-methyl-4-phenylpyri-dinium ion (MPP+) and rotenone. Additionally, expression of GSK3β in the mitochondria itself caused a significant decrease in complex I activity and ATP production. Increased mitochondrial GSK3β activity also increased reactive oxygen species production and perturbed the mitochondrial morphology. Conversely, chemical inhibitors of GSK3β inhibited MPP+- and rotenone-induced apoptosis, and attenuated the mitochondrial GSK3β-mediated impairment in complex I. These results indicate that unregulated mitochondrial GSK3β activity can mimic some of the mitochondrial insufficiencies found in PD pathology.


Glycogen synthase kinase-3β Parkinson’s disease 1-Methyl-4-phenylpyridinium Rotenone Mitochondria NADH:ubiquinone oxidoreductase Complex I Caspase-3 Reactive oxygen species Apoptosis 


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Copyright information

© Springer 2008

Authors and Affiliations

  • Taj D. King
    • 1
  • Buffie Clodfelder-Miller
    • 2
  • Keri A. Barksdale
    • 3
  • Gautam N. Bijur
    • 1
  1. 1.Department of Psychiatry and Behavioral NeurobiologyUniversity of Alabama at BirminghamBirmingham
  2. 2.Department of Comprehensive Neuroscience CenterUniversity of Alabama at BirminghamBirmingham
  3. 3.Department of NeurobiologyUniversity of Alabama at BirminghamBirmingham

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