Unregulated Mitochondrial GSK3β Activity Results in NADH:Ubiquinone Oxidoreductase Deficiency

GSK3 beta 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 GSK3 beta activity on cell fate are well-established, but the effects of mitochondrial GSK3 beta activity on mitochondrial function and cell fate are unknown. Here we selectively expressed constitutively active GSK3 beta 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 GSK3 beta in the mitochondria itself caused a significant decrease in complex I activity and ATP production. Increased mitochondria) GSK3 beta activity also increased reactive oxygen species production and perturbed the mitochondrial morphology. Conversely, chemical inhibitors of GSK3 beta inhibited MPP+- and rotenone-induced apoptosis, and attenuated the mitochondrial GSK3 beta-mediated impairment in complex I. These results indicate that unregulated mitochondrial GSK3 beta activity can mimic some of the mitochondria) insufficiencies found in PD pathology.