Regulation of Bcl-xL-ATP Synthase Interaction by Mitochondrial Cyclin B1-Cyclin-Dependent Kinase-1 Determines Neuronal Survival
| Autor: | Miguel Veas-Pérez de Tudela, Daniel Jimenez-Blasco, Veronica Bobo-Jimenez, Carolina Maestre, Angeles Almeida, Juan P. Bolaños, Rebeca Vecino, Maria Delgado-Esteban |
|---|---|
| Přispěvatelé: | European Commission, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III |
| Rok vydání: | 2015 |
| Předmět: |
Bcl-XL
Cell Survival Cyclin D Blotting Western Cyclin A bcl-X Protein Apoptosis Transfection F1Fo-ATP synthase CDC2 Protein Kinase Animals Immunoprecipitation RNA Small Interfering Rats Wistar Excitotoxicity Neurodegeneration Cyclin B1 Cells Cultured Adenosine Triphosphatases Neurons Cyclin-dependent kinase 1 biology Reverse Transcriptase Polymerase Chain Reaction General Neuroscience 1. No poverty Articles Flow Cytometry Immunohistochemistry Molecular biology Cyclin-Dependent Kinases Rats Mitochondria 3. Good health Cell biology Ubiquitin ligase Oxidative Stress Proteasome Nerve Degeneration Mutagenesis Site-Directed biology.protein Cyclin-dependent kinase complex Cyclin A2 Protein Binding |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.4712-14.2015 |
| Popis: | The survival of postmitotic neurons needs continuous degradation of cyclin B1, a mitotic protein accumulated aberrantly in the damaged brain areas of Alzheimer's disease and stroked patients. Degradation of cyclin B1 takes place in the proteasome after ubiquitylation by the anaphase-promoting complex/cyclosome (APC/C)–cadherin 1 (Cdh1), an E3 ubiquitin ligase that is highly active in neurons. However, during excitotoxic damage—a hallmark of neurological disorders—APC/C–Cdh1 is inactivated, causing cyclin B1 stabilization and neuronal death through an unknown mechanism. Here, we show that an excitotoxic stimulus in rat cortical neurons in primary culture promotes cyclin B1 accumulation in the mitochondria, in which it binds to, and activates, cyclin-dependent kinase-1 (Cdk1). The cyclin B1–Cdk1 complex in the mitochondria phosphorylates the anti-apoptotic protein B-cell lymphoma extra-large (Bcl-xL), leading to its dissociation from the β subunit of F1Fo–ATP synthase. The subsequent inhibition of ATP synthase activity causes complex I oxidative damage, mitochondrial inner membrane depolarization, and apoptotic neuronal death. These results unveil a previously unrecognized role for mitochondrial cyclin B1 in the oxidative damage associated with neurological disorders. This work was funded by Instituto de Salud Carlos III Grants PI12/00685 and RD12/0014/0007 (A.A.P.), RD12/0043/0021 (J.P.B.), FI10/00492 (M.V.-P.d.T.), and CP14/00010 (M.D.-E.), Ministerio de Economia y Competitividad Grant SAF2013-41177-R (J.P.B.), SP3-People-MC-ITN programme of the European Commission Grant 608381 (J.P.B.), and the European Regional Development Fund. |
| Databáze: | OpenAIRE |
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