Cyclic AMP‐Responsive Element Binding Protein in Brain Mitochondria

Cammarota, Martı́n; Paratcha, Gustavo; Bevilaqua, Lia R.; Stein, Miguelina Levi de; López, Margarita; Iraldi, Amanda Pellegrino de; Izquierdo, Iván; Medina, Jorge H.

doi:10.1046/j.1471-4159.1999.0722272.x

Cited by 88 publications

(82 citation statements)

References 23 publications

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“…The presence in mitochondria of transcription factors having a major role in neuronal survival, differentiation, and plasticity is an established, yet intriguing, notion that underlines the interplay among mitochondrial, nuclear, and cellular functions. Examples are the cAMP response element-binding protein (24) and p53 (25), as well as FOXO3a and FoxP2, members, such as Foxg1, of the Forkhead family (26,27).…”

Section: Discussionmentioning

confidence: 99%

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

Pancrazi

Benedetto

Colombaioni

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Forkhead box g1 (Foxg1) is a nuclear-cytosolic transcription factor essential for the forebrain development and involved in neurodevelopmental and cancer pathologies. Despite the importance of this protein, little is known about the modalities by which it exerts such a large number of cellular functions. Here we show that a fraction of Foxg1 is localized within the mitochondria in cell lines, primary neuronal or glial cell cultures, and in the mouse cortex. Import of Foxg1 in isolated mitochondria appears to be membrane potential-dependent. Amino acids (aa) 277-302 were identified as critical for mitochondrial localization. Overexpression of full-length Foxg1 enhanced mitochondrial membrane potential (ΔΨm) and promoted mitochondrial fission and mitosis. Conversely, overexpression of the C-term Foxg1 (aa 272-481), which is selectively localized in the mitochondrial matrix, enhanced organelle fusion and promoted the early phase of neuronal differentiation. These findings suggest that the different subcellular localizations of Foxg1 control the machinery that brings about cell differentiation, replication, and bioenergetics, possibly linking mitochondrial functions to embryonic development and pathological conditions.Rett syndrome | autism | cancer | brain cortex | development

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Section: Discussionmentioning

confidence: 99%

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

Pancrazi

Benedetto

Colombaioni

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Isolation of Mitochondria-Mitochondria were isolated from primary cultured cortical neurons and adult rat brains by sucrose density gradient centrifugation (6).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

Lee

Kim

Simon

et al. 2005

Journal of Biological Chemistry

187

153

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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.The cAMP response element-binding protein (CREB) 3 is a transcription factor known to mediate stimulus-dependent expression of genes critical for the plasticity, growth, and survival of neurons (1). A variety of stimuli alter levels of intracellular second messengers in neurons, such as cAMP and calcium, and activate CREB by leading to phosphorylation at its critical regulatory site, serine 133 (2, 3). Overexpression of constitutively active CREB prevents cell death induced by growth factor deprivation, while expression of a dominant negative form of CREB leads to apoptosis in both sympathetic neurons and cerebellar granule cells (4,5). A recent report that CREB is present in the mitochondria raises the possibility that CREB could mediate mitochondrial gene expression (6). Nonetheless, the function of mitochondrial CREB is not known. The present study confirms the presence of CREB in the mitochondria and addresses the role of CREB in mitochondrial gene expression and neuronal survival. The results raise the possibility of a novel mechanism for CREB dysfunction in the pathogenesis of neurodegenerative disorders. MATERIALS AND METHODSIsolation of Mitochondria-Mitochondria were isolated from primary cultured cortical neurons and adult rat brains by sucrose density gradient centrifugation (6).Confocal Microscopy-Indirect labeling methods were used to determine the levels of CREB, phosphorylated CREB (pCREB), and neurofilament (200 kDa) in cortical neuronal cultures and human and rat brain tissues as described previously (7).Immunogold Labeling and Electron Microscopy-Frozen samples were sectioned at Ϫ120°C, and the sections were transferred to Formvar/carboncoated copper grids. Samples were incubated with antibody in 1% bovine serum albumin for 30 min. After rinsing the samples four times with PBS, protein A-gold (10 nm) in 1% bovine serum albumin was added for 20 min. Contrasting stain procedures were carried out using 2% methyl cellulose: 3% uranyl acetate (9:1) for 10 min on ice. To dry the samples, grid...

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“…p65 and p50 were found in the mitochondria of resting liver cells [4], contrary to the p50 nucleo-cytosolic distribution in our model. CREB was detected in the mitochondria of the rat brain [1], while we observed a strictly nuclear localization for this protein in immature T cells. This data reveals the complexity of this phenomenon and suggests that the mitochondrial localization of transcription factors is under strict control and depends on the cell type and development stage.…”

Section: Discussionmentioning

confidence: 46%

“…An increasing number of reports reveal that "nuclear" transcription factors can also undergo translocation to the mitochondria under certain conditions. Some of these proteins, such as CREB [1], estrogen receptor [2], AP-1 [3] and NFκB [4], were found to bind mitochondrial DNA, while the localization of Nur77 [5], GR [6], p53 [7] and Elk-1 [8] to the mitochondrial membrane was found to be linked to the induction of apoptosis or decreased cell viability. In T cells, the increase in the intracellular calcium level upon T-cell receptor (TCR) engagement, mimicked by ionomycin treatment, activates calcineurin [9] and subsequently multiple transcription factors, including Nur77, NFκB and NFAT.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial localization of RelB and NFATx in immature T cells

Stasik

Rapak

Zioło

et al. 2008

Cellular and Molecular Biology Letters

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Abstract:In order to exert their activity, transcription factors must be transported to the nucleus. Certain transcription factors have also been found on mitochondria. Here, the localization of RelB and NFATx in the mitochondrial fractions of normal thymocytes and thymic lymphoma cells is shown for the first time. CREB was only found in the nucleus, while p50 (NFκB) was found in both the nucleus and the cytoplasm, but outside the mitochondria. The translocation of transcription factors to the mitochondria is differentially regulated. Unlike RelB, which is always present in the mitochondrial fraction, NFATx appeared on the mitochondria in cells treated with ionomycin together with an immunosuppressant and inhibitor of calcineurin (FK506). This data reveals that the mitochondrial localization of some transcription factors is precisely controlled by a calcium signal sensitive to FK506 in T cells.

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Cyclic AMP‐Responsive Element Binding Protein in Brain Mitochondria

Cited by 88 publications

References 23 publications

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

Foxg1 localizes to mitochondria and coordinates cell differentiation and bioenergetics

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

The mitochondrial localization of RelB and NFATx in immature T cells

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