Death-associated protein kinase as a sensor of mitochondrial membrane potential: role of lysosome in mitochondrial toxin-induced cell death.
We have investigated here the mechanism of dephosphorylation and activation of death-associated protein kinase (DAPK) and the role of lysosome in neuroblastoma cells (SH-SY5Y) treated with mitochondrial toxins, such as MPP(+) and rotenone. Mitochondrial respiratory chain inhibitors and uncouplers decreased mitochondrial membrane potential leading to DAPK dephosphorylation and activation. The class III phosphoinositide 3-kinase inhibitors attenuated DAPK dephosphorylation induced by mitochondrial toxins. Complex I inhibition by mitochondrial toxins (e.g. MPP(+)) resulted in mitochondrial swelling and lysosome reduction. Inhibition of class III phosphoinositide 3-kinase attenuated MPP(+)-induced lysosome reduction and cell death. The role of DAPK as a sensor of mitochondrial membrane potential in mitochondrial diseases was addressed.
Shang
Tiesong
T
Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Joseph
Joy
J
Hillard
Cecilia J
CJ
Kalyanaraman
B
B
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000154:Aconitate Hydratase / Q000378:metabolism; D000968:Antimycin A / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases; D004579:Electron Transport; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology*; D008564:Membrane Potentials; D008854:Microscopy, Electron; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012402:Rotenone / Q000494:pharmacology; D013347:Subcellular Fractions; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014118:Toxins, Biological / Q000494:pharmacology
D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014118:Toxins, Biological; D012402:Rotenone; D000968:Antimycin A; D019869:Phosphatidylinositol 3-Kinases; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000154:Aconitate Hydratase; C022616:thiazolyl blue; D015655:1-Methyl-4-phenylpyridinium