TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB–Dependent Activation of OPA1 Expression

Nan, Jinliang; Hu, Hengxun; Sun, Yong; Zhu, Long‐Guan; Wang, Yingchao; Zhong, Zhiwei; Zhao, Jing; Zhang, Na; Wang, Ya; Wang, Yaping; Ye, Jian; Zhang, Ling; Hu, Xinyang; Zhu, Wei; Wang, Jianan

doi:10.1161/circresaha.117.311143

Cited by 77 publications

(75 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The exposure to leptin improves the mitochondrial function in MCF-7 cells and ob/ob mice 16 , 17 . In transverse aortic constriction models, mitochondria are regulated by STAT3, which is a canonical downstream intermediate of leptin signaling pathway 18 .…”

Section: Introductionmentioning

confidence: 99%

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

Yang

Jiang

et al. 2018

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.

show abstract

Section: Introductionmentioning

confidence: 99%

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

Yang

Jiang

et al. 2018

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Notably, several studies have also found that TNFα treatment also activated mitochondrial fusion in human kidney-2 cells 51 and cardiomyocytes. 52 These results establish the various effects of TNFα on mitochondrial fission and mitochondrial fusion. This seems to be dependent on cell types.…”

Section: Discussionmentioning

confidence: 60%

TNFα promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK–ERK–YAP signaling pathways

Lu¹,

Chen²,

Wang³

et al. 2018

OTT

View full text Add to dashboard Cite

Background and objectiveThe present study was designed to explore the roles of mitochondrial fission and MAPK–ERK–YAP signaling pathways and to determine their mutual relationship in TNFα-mediated glioblastoma mitochondrial apoptosis.Materials and methodsCellular viability was measured via TUNEL staining, MTT assays, and Western blot. Immunofluorescence was performed to observe mitochondrial fission. YAP overexpression assays were conducted to observe the regulatory mechanisms of MAPK–ERK–YAP signaling pathways in mitochondrial fission and glioblastoma mitochondrial apoptosis.ResultsThe results in our present study indicated that TNFα treatment dose dependently increased the apoptotic rate of glioblastoma cells. Functional studies confirmed that TNFα-induced glioblastoma apoptosis was attributable to increased mitochondrial fission. Excessive mitochondrial fission promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, repressed ATP metabolism, elevated ROS synthesis, and downregulated antioxidant factors. In addition, the fragmented mitochondria liberated cyt-c into the cytoplasm/nucleus where it activated a caspase-9-involved mitochondrial apoptosis pathway. Furthermore, our data identified MAPK–ERK–YAP signaling pathways as the primary molecular mechanisms by which TNFα modulated mitochondrial fission and glioblastoma apoptosis. Reactivation of MAPK–ERK–YAP signaling pathways via overexpression of YAP neutralized the cytotoxicity of TNFα, attenuated mitochondrial fission, and favored glioblastoma cell survival.ConclusionOverall, our data highlight that TNFα-mediated glioblastoma apoptosis stems from increased mitochondrial fission and inactive MAPK–ERK–YAP signaling pathways, which provide potential targets for new therapies against glioblastoma.

show abstract

“…55 We identified a TNF-binding protein in the inner mitochondrial membrane that can be detected by a monoclonal antibody to TNFR2. Our EM data showing disrupted mitochondrial morphology in the absence of TNFR2/STAT3 signals further supports our line of thought.…”

Section: Cd133+mentioning

confidence: 96%

“…Previous studies have shown TNFR2 to confer mitochondria-dependent cardioprotective effects via STAT3 activation. 55 We identified a TNF-binding protein in the inner mitochondrial membrane that can be detected by a monoclonal antibody to TNFR2. 6 The mechanism by which TNFR2 is recruited to the mitochondria is unclear.…”

Section: Nk-cd133+ Cells Ccrcc-cd133+ Cscsmentioning

confidence: 96%

Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 ⁺ cells in clear cell renal carcinoma

et al. 2020

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) contains cancer stem‐like cells (CSCs) that express CD133 (ccRCC‐CD133+). CSCs are rarely in cell cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported that tumor necrosis factor receptor‐2 (TNFR2) signaling promotes the cell cycle entry of ccRCC‐CD133+CSCs, rendering them susceptible to cell‐cycle‐dependent chemotherapeutics. Here, we describe a TNFR2‐activated signaling pathway in ccRCC‐CD133+CSCs that is required for cell survival. Wild‐type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine727 but not tyrosine705, resulting in pSTAT3Ser727 translocation to and colocalization with TNFR2 in mitochondria. R2TNF signaling activates a kinase cascade involving the phosphorylation of VEGFR2, PI‐3K, Akt, and mTORC. Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNEL+cells expressing phosphorylated mixed lineage kinase‐like (MLKL). Pretreatment with necrostatin‐1 is more protective than z‐VAD.fmk, suggesting that most death is necroptotic and TNFR2 signaling promotes cell survival by preventing mitochondrial‐mediated necroptosis. These data suggest that a TNFR2 selective agonist may offer a potential therapeutic strategy for ccRCC.

show abstract

TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB–Dependent Activation of OPA1 Expression

Abstract: Supplemental Digital Content is available in the text.

Cited by 77 publications

References 79 publications

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

TNFα promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK–ERK–YAP signaling pathways

Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 ⁺ cells in clear cell renal carcinoma

Contact Info

Product

Resources

About

TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB–Dependent Activation of OPA1 Expression

Abstract: Supplemental Digital Content is available in the text.

Cited by 77 publications

References 79 publications

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation

TNF&alpha; promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK&ndash;ERK&ndash;YAP signaling pathways

Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 + cells in clear cell renal carcinoma

Contact Info

Product

Resources

About

TNFα promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK–ERK–YAP signaling pathways

Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 ⁺ cells in clear cell renal carcinoma