Differential insult-dependent recruitment of the intrinsic mitochondrial pathway during neuronal programmed cell death |
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Authors: | S Diwakarla P Nagley M L R Hughes B Chen P M Beart |
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Institution: | (1) Brian Injury and Repair Program, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria, 3010, Australia;(2) Department of Pharmacology, The University of Melbourne, Parkville, Victoria, 3010, Australia;(3) Biochemistry and Molecular Biology, Monash University, PO Box 13D, Parkville, Victoria, 3800, Australia;(4) Victorian College of Pharmacy, Monash University, Parkville, Victoria, 3052, Australia |
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Abstract: | Programmed cell death contributes to neurological diseases and may involve mitochondrial dysfunction with redistribution of
apoptogenic proteins. We examined neuronal death to elucidate whether the intrinsic mitochondrial pathway and the crosstalk
between caspase-dependent/-independent injury was differentially recruited by stressors implicated in neurodegeneration. After
exposure of cultured cerebellar granule cells to various insults, the progression of injury was correlated with mitochondrial
involvement, including the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Injury
occurred across a continuum from Bax- and caspase-dependent (trophic- factor withdrawal) to Bax-independent, calpain-dependent
(excitotoxicity) injury. Trophic-factor withdrawal produced classical recruitment of the intrinsic pathway with activation
of caspase-3 and redistribution of cytochrome c, whereas excitotoxicity induced early redistribution of AIF and HtrA2/Omi,
elevation of intracellular calcium and mitochondrial depolarization. Patterns of engagement of neuronal programmed cell death
and the redistribution of mitochondrial IMS proteins were canonical, reflecting differential insult-dependencies.
Received 14 August 2008; received after revision 02 October 2008; accepted 23 October 2008 |
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Keywords: | " target="_blank"> Cell death neurons excitotoxicity mitochondrial membrane potential Bax proteases cytochrome c AIF |
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