Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium.
The compound 1-methyl-4-phenylpyridinium (MPP) is a selective inhibitor of mitochondrial complex I, and is widely used in model systems to elicit neurochemical alterations that may be associated with Parkinson's disease. In the present study treatment of human neuroblastoma SH-SY5Y cells with MPP resulted in a time- and concentration-dependent activation of the apoptosis-associated cysteine protease caspase-3, and caused morphological changes characteristic of apoptosis. To test if the activation state of the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway affects MPP-induced caspase-3 activation, PI3K was inhibited with LY294002, or activated with insulin-like growth factor-1. MPP-induced caspase-3 activation was increased by inhibition of PI3K, and decreased by stimulation of PI3K, indicative of anti-apoptotic signaling by the PI3K/Akt pathway. To test if glycogen synthase kinase-3beta (GSK3beta), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3beta and lithium, a selective inhibitor of GSK3beta, were used to directly alter GSK3beta activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3beta. Conversely, the GSK3beta inhibitor lithium attenuated MPP-induced caspase-3 activation. To test if these regulatory interactions applied to other mitochondrial complex I inhibitors, cells were treated with rotenone. Rotenone-induced activation of caspase-3 was enhanced by inhibition of PI3K or increased GSK3beta activity, and was attenuated by inhibiting GSK3beta with lithium. Overall, these results indicate that inhibition of GSK3beta provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.
King
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TD
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294, USA.
Bijur
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GN
Jope
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D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D004357:Drug Synergism; D042967:Electron Transport Complex I; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D009025:Morpholines / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002867:Chromones; D004791:Enzyme Inhibitors; D006540:Herbicides; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012402:Rotenone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D008094:Lithium; D009247:NADH, NADPH Oxidoreductases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D042967:Electron Transport Complex I; D015655:1-Methyl-4-phenylpyridinium