Abstract:
:GSK3beta 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 GSK3beta activity on cell fate are well-established, but the effects of mitochondrial GSK3beta activity on mitochondrial function and cell fate are unknown. Here we selectively expressed constitutively active GSK3beta 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-phenylpyridinium ion (MPP+) and rotenone. Additionally, expression of GSK3beta in the mitochondria itself caused a significant decrease in complex I activity and ATP production. Increased mitochondrial a GSK3beta activity also increased reactive oxygen species production and perturbed the mitochondrial morphology. Conversely, chemical inhibitors of GSK3beta inhibited MPP+- and rotenone-induced apoptosis, and attenuated the mitochondrial GSK3beta-mediated impairment in complex I. These results indicate that unregulated mitochondrial GSK3beta activity can mimic some of the mitochondrial insufficiencies found in PD pathology.
journal_name
Neurotox Resjournal_title
Neurotoxicity researchauthors
King TD,Clodfelder-Miller B,Barksdale KA,Bijur GNdoi
10.1007/BF03033861subject
Has Abstractpub_date
2008-12-01 00:00:00pages
367-82issue
4eissn
1029-8428issn
1476-3524journal_volume
14pub_type
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