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Mitochondrial glycogen synthase kinase‐3beta: an investigation into its role in metabolism and cell fate
Author(s) -
ClodfelderMiller Buffie J,
King Taj D,
Bijur Gautam N
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.801.3
Subject(s) - microbiology and biotechnology , mitochondrion , apoptosis , gsk 3 , gsk3b , biology , glycogen synthase , cytosol , signal transduction , programmed cell death , phosphorylation , chemistry , biochemistry , enzyme
Glycogen synthase kinase‐3ß (GSK3ß) facilitates apoptosis signaling and also regulates cell metabolism. GSK3ß is mostly in the cytosol, but an active pool of GSK3ß is present in the mitochondria. The present study focuses on the unknown actions of GSK3ß in mitochondria. A novel strategy was employed using a lentivirus gene delivery to express an inducible mitochondrial‐targeted, active GSK3ß (mS9AGSK3ß) in neuroblastoma cells. Immunofluorescence microscopy confirmed that mS9AGSK3ß was specifically localized in mitochondria. Increased expression of mS9AGSK3ß by itself did not activate apoptosis. However, increased expression of mS9AGSK3ß significantly enhanced apoptosis and cell death when cells were cultured under conditions of reduced glycolysis. It was also found that mS9AGSK3ß expression greatly facilitated apoptosis induced by the oxidative phosphorylation complex I inhibitors MPP and rotenone, and inhibition of GSK3? activity with lithium blocked apoptosis. Thus, increased GSK3ß activity in the mitochondria is deleterious under conditions that increase mitochondrial function and during mitochondrial stress. Support by NARSAD, NIH‐NINDS, and the NIH Neuroscience Blueprint Core Grant NS57098.