title: Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival.
abstract: Cyclic AMP response element-binding protein (CREB) is a widely expressed transcription factor whose role in neuronal protection is now well established. Here we report that CREB is present in the mitochondrial matrix of neurons and that it binds directly to cyclic AMP response elements (CREs) found within the mitochondrial genome. Disruption of CREB activity in the mitochondria decreases the expression of a subset of mitochondrial genes, including the ND5 subunit of complex I, down-regulates complex I-dependent mitochondrial respiration, and increases susceptibility to 3-nitropropionic acid, a mitochondrial toxin that induces a clinical and pathological phenotype similar to Huntington disease. These results demonstrate that regulation of mitochondrial gene expression by mitochondrial CREB, in part, underlies the protective effects of CREB and raise the possibility that decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders.
authors.affiliation: Neurology Department, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Junghee
authors.initials: J
authors.lastname: Lee
authors.forename: Chun-Hyung
authors.initials: CH
authors.lastname: Kim
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
authors.forename: Lyaylya R
authors.initials: LR
authors.lastname: Aminova
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Andreyev
authors.forename: Yulia E
authors.initials: YE
authors.lastname: Kushnareva
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.forename: Bonnie E
authors.initials: BE
authors.lastname: Lonze
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: David D
authors.initials: DD
authors.lastname: Ginty
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000648:ultrastructure*; D002470:Cell Survival; D002540:Cerebral Cortex / Q000166:cytology; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000235:genetics / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D009574:Nitro Compounds / Q000494:pharmacology; D010101:Oxygen Consumption / Q000502:physiology; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004272:DNA, Mitochondrial; D009574:Nitro Compounds; D011422:Propionates; D000242:Cyclic AMP; D042967:Electron Transport Complex I; C015392:3-nitropropionic acid