Meuer, K. et al. Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis. Cell Death Differ. 14, 651-661

Universitätsmedizin Göttingen, Göttingen, Lower Saxony, Germany
Cell Death and Differentiation (Impact Factor: 8.18). 05/2007; 14(4):651-61. DOI: 10.1038/sj.cdd.4402087
Source: PubMed


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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Available from: Gunnar P H Dietz
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    • "Activation of Cdk5 plays an early role in the cell death cascade before the initiation of mitochondrial dysfunction, and Cdk5 inhibition prevents the mitochondrial damage and cell death caused by Prx2 inactivationmediated oxidative stress (Sun et al. 2008). Interestingly, Cdk5 also regulates mitochondrial fission during neuronal apoptosis as an upstream signaling kinase (Meuer et al. 2007). However, the precise mechanism by which Cdk5 regulates mitochondrial morphology is still unclear. "
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    ABSTRACT: Mitochondrial dysfunction is implicated in age-related degenerative disorders such as Alzheimer's disease (AD). Maintenance of mitochondrial dynamics is essential for regulating mitochondrial function. Aβ oligomers (AβOs), the typical cause of AD, lead to mitochondrial dysfunction and neuronal loss. AβOs have been shown to induce mitochondrial fragmentation, and their inhibition suppresses mitochondrial dysfunction and neuronal cell death. Oxidative stress is one of the earliest hallmarks of AD. Cyclin-dependent kinase 5 (Cdk5) may cause oxidative stress by disrupting the antioxidant system, including Prx2. Cdk5 is also regarded as a modulator of mitochondrial fission; however, a precise mechanistic link between Cdk5 and mitochondrial dynamics is lacking. We estimated mitochondrial morphology and alterations in mitochondrial morphology-related proteins in N2a cells stably expressing the swedish mutation of amyloid precursor protein (APP), which is known to increase AβO production. We demonstrated that mitochondrial fragmentation by AβOs accompanies reduced Mfn1 and Mfn2 levels. Interestingly, the Cdk5 pathway, including phosphorylation of the Prx2-related oxidative stress, has been shown to regulate Mfn1 and Mfn2 levels. Furthermore, Mfn2, but not Mfn1, overexpression significantly inhibits the AβO-mediated cell death pathway. Therefore, these results indicate that AβO-mediated oxidative stress triggers mitochondrial fragmentation via decreased Mfn2 expression by activating Cdk5-induced Prx2 phosphorylation.
    Full-text · Article · Oct 2014 · Journal of Neurochemistry
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    • "However, several reports have demonstrated that CDK5 is involved in the regulation of mitochondrial dynamics in various pathological conditions. For example, CDK5 can induce Drp1-mediated mitochondrial fragmentation during neuronal cell death38 by promoting S-nitrosylation of Drp1.39 However, the effect of CDK5 on Drp1 phosphorylation has not been examined under physiological conditions. "
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    ABSTRACT: Mitochondrial functions are essential for the survival and function of neurons. Recently, it has been demonstrated that mitochondrial functions are highly associated with mitochondrial morphology, which is dynamically changed by the balance between fusion and fission. Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin-related protein 1 (Drp1), which promotes mitochondrial fission. Drp1 activity is regulated by several post-translational modifications, thereby modifying mitochondrial morphology. Here, we found that phosphorylation of Drp1 at serine 616 (S616) is mediated by cyclin-dependent kinase 5 (CDK5) in post-mitotic rat neurons. Perturbation of CDK5 activity modified the level of Drp1(S616) phosphorylation and mitochondrial morphology in neurons. In addition, phosphorylated Drp1(S616) preferentially localized as a cytosolic monomer compared with total Drp1. Furthermore, roscovitine, a chemical inhibitor of CDKs, increased oligomerization and mitochondrial translocation of Drp1, suggesting that CDK5-dependent phosphorylation of Drp1 serves to reduce Drp1's fission-promoting activity. Taken together, we propose that CDK5 has a significant role in the regulation of mitochondrial morphology via inhibitory phosphorylation of Drp1(S616) in post-mitotic neurons.
    Full-text · Article · Jul 2014 · Experimental and Molecular Medicine
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    • "This aspect takes more importance if transnitrosation does not occur with low-molecular-weight thiols, but takes place between proteins. Indeed, this reaction is responsible for the propagation of many NO-mediated cell signaling pathways and its significance has been highlighted quite recently in many physiopathological processes, such as (i) NO exchange between hemoglobin and the anion exchanger 1, which mediates NO release from erythrocytes [28]; (ii) transnitrosation among thioredoxin (Trx), caspase-3 and the inhibitor of apoptosis (IAPs) proteins, which is involved in the regulation of cell death by apoptosis [27, 29–31]; (iii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-mediated S-nitrosation of nuclear proteins, which contributes to cell death and accounts for the pathogenesis of several neurodegenerative diseases [32, 33]; (iv) transnitrosation between the neuronal-specific cyclin dependent kinase 5 (Cdk5) and dynamin-related protein 1 (Drp1), which plays a pivotal role in mitochondrial dysfunction typical of neurodegenerations [26, 34]. "
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    ABSTRACT: Protein S-nitrosation is deemed as a prototype of posttranslational modifications governing cell signaling. It takes place on specific cysteine residues that covalently incorporate a nitric oxide (NO) moiety to form S-nitrosothiol derivatives and depends on the ratio between NO produced by NO synthases and nitrosothiol removal catalyzed by denitrosating enzymes. A large number of cysteine-containing proteins are found to undergo S-nitrosation and, among them, the enzymes catalyzing ubiquitination, mainly the class of ubiquitin E3 ligases and the 20S component of the proteasome, have been reported to be redox modulated in their activity. In this review we will outline the processes regulating S-nitrosation and try to debate whether and how it affects protein ubiquitination and degradation via the proteasome. In particular, since muscle and neuronal health largely depends on the balance between protein synthesis and breakdown, here we will discuss the impact of S-nitrosation in the efficiency of protein quality control system, providing lines of evidence and speculating about its involvement in the onset and maintenance of neuromuscular dysfunctions.
    Full-text · Article · Jan 2014 · International Journal of Cell Biology
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