Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3β and attenuated by lithium

Taj D. King, Gautam N. Bijur, Richard S Jope

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

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-3β (GSK3β), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3β and lithium, a selective inhibitor of GSK3β, were used to directly alter GSK3β activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3β. Conversely, the GSK3β 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 GSK3β activity, and was attenuated by inhibiting GSK3β with lithium. Overall, these results indicate that inhibition of GSK3β provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.

Original languageEnglish
Pages (from-to)106-114
Number of pages9
JournalBrain Research
Volume919
Issue number1
DOIs
StatePublished - Nov 16 2001
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
1-Methyl-4-phenylpyridinium
Lithium
Caspase 3
Phosphatidylinositol 3-Kinase
Rotenone
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Cysteine Proteases
Poisons
Somatomedins
Neuroblastoma
Parkinson Disease
Cell Survival
Phosphotransferases

Keywords

  • Glycogen synthase kinase
  • Lithium
  • MPP
  • Parkinson's disease
  • Rotenone

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3β and attenuated by lithium. / King, Taj D.; Bijur, Gautam N.; Jope, Richard S.

In: Brain Research, Vol. 919, No. 1, 16.11.2001, p. 106-114.

Research output: Contribution to journalArticle

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abstract = "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-3β (GSK3β), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3β and lithium, a selective inhibitor of GSK3β, were used to directly alter GSK3β activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3β. Conversely, the GSK3β 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 GSK3β activity, and was attenuated by inhibiting GSK3β with lithium. Overall, these results indicate that inhibition of GSK3β provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.",
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