Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival.
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.
Lee
Junghee
J
Neurology Department, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Kim
Chun-Hyung
CH
Simon
David K
DK
Aminova
Lyaylya R
LR
Andreyev
Alexander Y
AY
Kushnareva
Yulia E
YE
Murphy
Anne N
AN
Lonze
Bonnie E
BE
Kim
Kwang-Soo
KS
Ginty
David D
DD
Ferrante
Robert J
RJ
Ryu
Hoon
H
Ratan
Rajiv R
RR
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
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