Unregulated mitochondrial GSK3beta activity results in NADH: ubiquinone oxidoreductase deficiency.
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.
King
Taj D
TD
Department of Psychiatry and Behavioral Neurobiology, Comprehensive Neuroscience Center and Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Clodfelder-Miller
Buffie
B
Barksdale
Keri A
KA
Bijur
Gautam N
GN
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D042967:Electron Transport Complex I / Q000172:deficiency*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology
D017382:Reactive Oxygen Species; D012402:Rotenone; D000255:Adenosine Triphosphate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium