Journal
CELL DEATH AND DIFFERENTIATION
Volume 14, Issue 4, Pages 651-661Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4402087
Keywords
mitochondrial fission; neuroprotection; cyclin-dependent kinase; neuronal apoptosis; cyclin-dependent kinase inhibitors; neurodegeneration
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Under physiological conditions, mitochondrial morphology dynamically shifts between a punctuate appearance and tubular networks. However, little is known about upstream signal transduction pathways that regulate mitochondrial morphology. We show that mitochondrial fission is a very early and kinetically invariant event during neuronal cell death, which causally contributes to cytochrome c release and neuronal apoptosis. Using a small molecule CDK5 inhibitor, as well as a dominant-negative CDK5 mutant and RNAi knockdown experiments, we identified CDK5 as an upstream signalling kinase that regulates mitochondrial fission during apoptosis of neurons. Vice versa, our study shows that mitochondrial fission is a modulator contributing to CDK5-mediated neurotoxicity. Thereby, we provide a link that allows integration of CDK5 into established neuronal apoptosis pathways.
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