Prohibitin 1 modulates mitochondrial function of Stat3

Han, Jie; Yu, Chunhua; Souza, Rhonda F.; Theiss, Arianne L.

doi:10.1016/j.cellsig.2014.06.006

Cited by 35 publications

(29 citation statements)

References 64 publications

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“…Complex I of the ETC is a predominant site of PHB binding, resulting in optimal activity of complex I and the respiratory chain. 11,13 Previous studies have shown that TNF α reduces PHB expression in IECs, 32,42 which we also confirm in the current study (Fig. 3).…”

Section: Discussionsupporting

confidence: 92%

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Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction

Han

Zhao

Basmadjian

et al. 2016

Inflammatory Bowel Diseases

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Background Flavaglines are a family of natural compounds shown to have anti-inflammatory and cytoprotective effects in neurons and cardiomyocytes. Flavaglines target prohibitins as ligands, which are scaffold proteins that regulate mitochondrial function, cell survival, and transcription. This study tested the therapeutic potential of flavaglines to promote intestinal epithelial cell homeostasis and to protect against a model of experimental colitis in which inflammation is driven by epithelial ulceration. Methods Survival and homeostasis of Caco2-BBE and IEC-6 intestinal epithelial cell lines were measured during treatment with the flavaglines FL3 or FL37 alone and in combination with the proinflammatory cytokines tumor necrosis factor (TNF) α and interferon γ. Wild-type mice were intraperitoneally injected with 0.1 mg/kg FL3 or vehicle once daily for 4 days during dextran sodium sulfate–induced colitis to test the in vivo anti-inflammatory effect of FL3. Results FL3 and FL37 increased basal Caco2-BBE and IEC-6 cell viability, decreased apoptosis, and decreased epithelial monolayer permeability. FL3 and FL37 inhibited TNFα- and interferon γ–induced nuclear factor kappa B and Cox2 expression, apoptosis, and increased permeability in Caco2-BBE cells. FL3 and FL37 protected against TNFα-induced mitochondrial superoxide generation by preserving respiratory chain complex I activity and prohibitin expression. p38-MAPK activation was essential for the protective effect of FL3 and FL37 on barrier permeability and mitochondrial-derived reactive oxygen species production during TNFα treatment. Mice administered FL3 during dextran sodium sulfate colitis exhibited increased colonic prohibitin expression and p38-MAPK activation, preserved barrier function, and less inflammation. Conclusions These results suggest that flavaglines exhibit therapeutic potential against colitis and preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.

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Section: Discussionsupporting

confidence: 92%

“…TNF α significantly increased mitoSOX fluorescence in Caco2-BBE cells, as shown previously. 32,33 Pretreatment with 10 nM FL3 or FL37 prevented TNF α -induced mitochondrial ROS production.…”

Section: Resultsmentioning

confidence: 98%

Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction

Han

Zhao

Basmadjian

et al. 2016

Inflammatory Bowel Diseases

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“…Depending on phosphorylation of residues S727 or Y705, STAT3 can inhibit or promote nuclear gene expression [23]. Recent seminal studies identified a non-transcriptional role of pS727-STAT3 in stimulating mitochondrial bioenergetic function through electron transport chain (ETC) complex I, II and V activity [24–26], probably not by binding directly [27], but by binding to prohibitin 1 [28]. STAT3 can also reduce formation of the mitochondrial permeability transition pore, possibly by interacting with cyclophilin D [29], thus maintaining membrane potential necessary for bioenergetic function, as well as preventing release of cytochrome-c, which leads to apoptosis [30].…”

Section: Introductionmentioning

confidence: 99%

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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“…STAT3 phosphorylated at serine 727 (Ser727) localizes in mitochondria (Yu et al, 2015). Mitochondrial P-STAT3 Ser is required for optimal electron transport chain (ETC) activity and protects against stress-induced mitochondrial dysfunction (Wegrzyn et al, 2009), such as increasing levels of reactive oxygen species (ROS) (Han et al, 2014). These findings indicate that STAT3 could have diverse roles, from conveying signals to the (1) nuclei by P-STAT3 Tyr to facilitate transcription of target genes such as SOCS3, and (2) mitochondria by P-STAT3 Ser to foster mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury

Park

Lin

Benveniste

et al. 2016

Experimental Neurology

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Suppressor of cytokine signaling-3 (SOCS3) expression is induced by the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. SOCS3 then acts as a feedback inhibitor of JAK-STAT signaling. Previous studies have shown that knocking down SOCS3 in spinal cord neurons with Lentiviral delivery of SOCS3-targeting shRNA (shSOCS3) increased spinal cord injury (SCI)-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr), which in part contributed to decreased neuronal death and demyelination as well as enhanced dendritic regeneration and protection of neuronal morphology after SCI. However, the role of serine phosphorylation of STAT3 (P-STAT3 Ser) is in large part undetermined. Our purposes of this study were to evaluate the expression patterns of P-STAT3 Ser and to explore the possible role of SOCS3 in the regulation of P-STAT3 Ser expression. Immunoblot analyses demonstrated that Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, induced both P-STAT3 Tyr and P-STAT3 Ser in SH-SY5Y cells. Subcellular fractionation further revealed that P-STAT3 Ser was localized in mitochondria. Overexpression of SOCS3 with a Lentivirus-mediated approach in SH-SY5Y cells inhibited OSM-induced P-STAT3 Ser in both cytosol and mitochondria fractions. In contrast, OSM-induced P-STAT3 Ser was further upregulated in both cytosol and mitochondria when SOCS3 was knocked down by Lentivirus-delivered shSOCS3. Using a rat T8 spinal cord complete transection model, we found that SCI induced upregulation of P-STAT3 Ser in the mitochondria of macrophages/microglia and neurons both rostral and caudal to the injury site of spinal cord. Collectively, these results suggest that SOCS3 regulation of STAT3 signaling plays critical roles in stress conditions.

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Prohibitin 1 modulates mitochondrial function of Stat3

Cited by 35 publications

References 64 publications

Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction

Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction

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

Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury

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