title: Regulation of Bcl-xL-ATP Synthase Interaction by Mitochondrial Cyclin B1-Cyclin-Dependent Kinase-1 Determines Neuronal Survival.
abstract: 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.
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Veas-Pérez de Tudela
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Delgado-Esteban
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and.
authors.forename: Carolina
authors.initials: C
authors.lastname: Maestre
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Bobo-Jiménez
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jiménez-Blasco
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Vecino
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolaños
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, and Institute of Functional Biology and Genomics, University of Salamanca-Spanish National Research Council, E-37007 Salamanca, Spain aaparra@usal.es.
authors.forename: Angeles
authors.identifier: http://orcid.org/0000-0003-0485-8904
authors.initials: A
authors.lastname: Almeida
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase; D002470:Cell Survival; D002478:Cells, Cultured; D056744:Cyclin B1 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009410:Nerve Degeneration / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C494813:Bcl2l1 protein, rat; C534701:Ccnb1 protein, rat; D056744:Cyclin B1; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D016203:CDC2 Protein Kinase; C548796:Cdk1 protein, rat; D018844:Cyclin-Dependent Kinases; D000251:Adenosine Triphosphatases
keywords: Bcl-xL; F1Fo-ATP synthase; cyclin B1; excitotoxicity; mitochondria; neurodegeneration