Abstract
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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Abbreviations
- CDK5:
-
cyclin-dependent kinase 5
- dCSM cells:
-
neuronally differentiated CSM14.1 cells
- Drp1:
-
dynamin-related protein 1
- dnDrp1:
-
dominant-negative mutant of dynamin-related protein 1
- MPP+:
-
1-methyl-4-phenylpyridinium ion
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Acknowledgements
We thank Jean-Claude Martinou and Manuel Rojo for the gift of Fis1 and Drp1 plasmids, and Pawel Kermer for CSM14.1 cells. p25, p35 and CDK5 constructs as well as p39 antibody were generously provided by Li-Huei Tsai. We also thank Christine Poser for excellent technical assistance. We thank Stefan W Hell for his continuous support (SJ). Funded by Deutsche Forschengsgemeinschaft through the DFG-Research Center for Molecular Physiologie of the Brain.
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Meuer, K., Suppanz, I., Lingor, P. et al. Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. Cell Death Differ 14, 651–661 (2007). https://doi.org/10.1038/sj.cdd.4402087
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DOI: https://doi.org/10.1038/sj.cdd.4402087
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