Stat3 Binds to mtDNA and Regulates Mitochondrial Gene Expression in Keratinocytes

Macías, Everardo; Rao, Dharanija; Carbajal, Steve; Kiguchi, Kaoru; DiGiovanni, John

doi:10.1038/jid.2014.68

Cited by 86 publications

(107 citation statements)

References 54 publications

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“…Our results with actinomycin are consistent with the known non-transcriptional nature of the role of STAT3 in mitochondrial function [24, 26], and support a non-transcriptional effect of FAK inhibition on mitochondria. In an apparent contradiction, in keratinocytes, S727-STAT3 can repress transcription of mitochondrial ETC genes, but no functional measures were reported [77]. Our finding that pS727-STAT3 is mainly found in the mitochondrial and nuclear fractions, but less in the cytoplasm, is consistent with the findings that STAT3 translocates upon S727 phosphorylation in the cytoplasm [53].…”

Section: Discussionsupporting

confidence: 83%

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

et al. 2016

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BackgroundSTAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof.MethodsCultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators. STAT3 null cells were transfected with mutant STAT3 plasmids. Outcome measures included oxygen consumption rate for mitochondrial bioenergetics, Western blotting for protein phosphorylation, mitochondrial membrane potential for mitochondrial integrity, ROS production, and cell counts.ResultsVitronectin-dependent mitochondrial basal respiration, ATP production, and maximum reserve and respiratory capacities were suppressed within 4 h by RGD and αvβ3 integrin antagonist peptides. Conversely, integrin ligands vitronectin, laminin and fibronectin stimulated mitochondrial function. Pharmacological inhibition of FAK completely abolished mitochondrial function within 4 h while FAK siRNA treatments confirmed the specificity of FAK signaling. WT, but not S727A functionally dead mutant STAT3, rescued bioenergetics in cells made null for STAT3 using CRISPR-Cas9. STAT3 inhibition with stattic in whole cells rapidly reduced mitochondrial function and mitochondrial pS727-STAT3. Stattic treatment of isolated mitochondria did not reduce pS727 whereas more was detected upon phosphatase inhibition. This suggests that S727-STAT3 is activated in the cytoplasm and is short-lived upon translocation to the mitochondria. FAK inhibition reduced pS727-STAT3 within mitochondria and reduced mitochondrial function in a non-transcriptional manner, as shown by co-treatment with actinomycin. Treatment with the small molecule bryostatin-1 or hepatocyte growth factor (HGF), which indirectly activate S727-STAT3, preserved mitochondrial function during FAK inhibition, but failed in the presence of the STAT3 inhibitor. FAK inhibition induced loss of mitochondrial membrane potential, which was counteracted by bryostatin, and increased superoxide and hydrogen peroxide production. Bryostatin and HGF reduced the substantial cell death caused by FAK inhibition over a 24 h period.ConclusionThese data suggest that extracellular matrix molecules promote STAT3-dependent mitochondrial function and cell survival through integrin-FAK signaling. We furthermore show a new treatment strategy for cell survival using S727-STAT3 activators.

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Section: Discussionsupporting

confidence: 83%

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

et al. 2016

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“…S2A). Longer-term treatment of cells with cytokines (16) or growth factors (5, 17, 18) drives an increase in mitoSTAT3 amounts. This effect was also recapitulated in MEFs stimulated with OSM for 2 hours, suggesting that acute and long-term exposure differentially regulated mitoSTAT3 (fig.…”

Section: Resultsmentioning

confidence: 99%

Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production

et al. 2017

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Signal transducer and activator of transcription 3 (STAT3) is associated with various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria, where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that the amounts of STAT3 in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended on phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the amino terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially localized STAT3 in sensing and responding to external stimuli.

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“…three nuclear encoded proteins: the monomeric RNA polymerase (RNAP) or POLRMT in humans, mitochondrial transcription factor A (TFAM), and mitochondrial transcription factor B1 and B2 (TFB1M, TFB2M). STAT3 immunoprecipitates with TFAM [42] and chromatin immunoprecipitation shows that STAT3 binds to mtDNA at both the regulatory D-loop of platelets [23] and at consensus STAT binding sites throughout the mitochondrial genome of keratinocytes [42]. Deletion of STAT3 from keratinocytes results in an increase in the expression of mtDNA encoded genes implying that STAT3 represses transcription of the mitochondrial genome (Fig.…”

Section: Stat3 Mitochondrial Functionsmentioning

confidence: 95%

Mitochondrial STAT3: Powering up a potent factor

et al. 2016

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The JAK-STAT3 signaling pathway is engaged by many cytokines and growth factor stimuli to control diverse biological processes including proliferation, angiogenesis, survival, immune modulation, and metabolism. For over two decades it has been accepted that STAT3-dependent biology is due to its potency as a transcription factor capable of regulating the expression of many hundreds of genes. However, recent evidence of non-canonical and non-genomic activities of STAT3 has emerged. The most exciting of these activities is its capacity to translocate into the mitochondria where it regulates the activity of the electron transport chain and the opening of the mitochondrial permeability transition pore. These have broad consequences including cell survival and the production of reactive oxygen species and ATP in both normal tissue and under pathological conditions. Despite these fascinating observations there are many key unanswered questions about the mechanism of STAT mitochondrial activity.

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Stat3 Binds to mtDNA and Regulates Mitochondrial Gene Expression in Keratinocytes

Cited by 86 publications

References 54 publications

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production

Mitochondrial STAT3: Powering up a potent factor

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