The Import of the Transcription Factor STAT3 into Mitochondria Depends on GRIM-19, a Component of the Electron Transport Chain

Tammineni, Prasad; Anugula, Chandrashekhar; Mohammed, Fareed; Murari, Anjaneyulu; Larner, Andrew C.; Sepuri, Naresh Babu V.

doi:10.1074/jbc.m112.378984

Cited by 184 publications

(218 citation statements)

References 48 publications

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“…Studies have identified a Stat3-Grim-19 complex in the nucleus, cytoplasm and mitochondria (Bu et al, 2013;Li et al, 2012;Lufei et al, 2003;Zhang et al, 2003). Indeed it has recently been demonstrated that Grim-19 is required for Stat3 translocation to the mitochondria (Tammineni et al, 2013). We have demonstrated that in cells undergoing TNFa-induced necroptosis, Stat3 is phosphorylated on serine 727 by the necrosome, composed of RIPK-3, and in some instances, RIPK-1 (Shulga and Pastorino, 2012).…”

Section: R E T R a C T I O Nmentioning

confidence: 75%

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Shulga

Pastorino

2013

Journal of Cell Science

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Fructose and ethanol are metabolized principally in the liver and are both known to contribute to the development of hepatic steatosis that can progress to hepatic steatohepatitis. The present study indentifies a synergistic interaction between fructose and ethanol in promoting hepatocyte sensitivity to TNFa-induced necroptosis. Concurrent exposure to fructose and ethanol induces the overexpression of the CDGSH iron-sulfur domain-containing protein 1 (CISD1 or mitoneet), which is localized to the outer mitochondrial membrane. The increased expression of mitoneet primes the hepatocyte for TNFa-induced cytotoxicity. Treatment with TNFa induces the translocation of a Stat3-Grim-19 complex to the mitochondria, which binds to mitoneet and promotes the rapid release of its 2Fe-2S cluster, causing an accumulation of mitochondrial iron. The dramatic increase of mitochondrial iron provokes a surge in formation of reactive oxygen species, resulting in mitochondrial injury and cell death. Additionally, mitoneet is constitutively expressed at high levels in L929 fibrosarcoma cells and is required for L929 cells to undergo TNFa-induced necroptosis in the presence of caspase inhibition, indicating the importance of mitoneet to the necroptotic form of cell death.

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Section: R E T R a C T I O Nmentioning

confidence: 75%

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Shulga

Pastorino

2013

Journal of Cell Science

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“…As Wegrzyn and colleagues 37 found, the immunoprecipitates of mitochondrial extracts yielded from mouse liver captured by a monoclonal antibody specifically targeted to the components of the ETC complex I contained STAT3 and NDUFA13. Using highly purified rat heart mitochondria in vitro, Tammineni et al 39 further discovered that STAT3 most likely resides in the inner mitochondrial membrane (IMM), facing toward the matrix. STAT3 import and translocation across the mitochondrial membrane requires membrane potential and, likely, energy.…”

Section: The Structure and Subcellular Localization Of Stat3mentioning

confidence: 99%

“…The C terminus of STAT3, especially Ser727, is required for the NDUFA13-dependent import and integration of STAT3 into complex I because mutating serine 727 to alanine reduces the import of STAT3 into mitochondria, even in the presence of NDUFA13. 39 …”

Section: The Structure and Subcellular Localization Of Stat3mentioning

confidence: 99%

The role of STAT3 in autophagy

et al. 2015

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Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

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“…It has already been shown that p53 can be imported into mitochondria by co-transport mechanisms via interaction with proteins such as mtHsp70, 19 Tid1, 68 mitochondrial helicase RECQL4, 60 or OKL38. 69 Furthermore, a very recent study described an import mechanism of the STAT3 nuclear protein into the mitochondrial matrix via an interaction with GRIM-19, a subunit of respiratory chain complex I, 70 supporting the fact that such proteins can also be involved in protein transport into mitochondria. However, the decrease of p53 in cells treated with siOSCP could depend on specific modifications of mitochondrial physiology due to OSCP knockdown.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F₁F₀-ATP synthase

Bergeaud¹,

Mathieu²,

Guillaume³

et al. 2013

Cell Cycle

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We and others previously reported that endogenous p53 can be located at mitochondria in the absence of stress, suggesting that p53 has a role in the normal physiology of this organelle. the aim of this study was to characterize in unstressed cells the intramitochondrial localization of p53 and identify new partners and functions of p53 in mitochondria. We find that the intramitochondrial pool of p53 is located in the intermembrane space and the matrix. of note, unstressed HCt116 p53+/+ cells simultaneously show increased o 2 consumption and decreased mitochondrial superoxide production compared with their p53-null counterpart. this data was confirmed by stable H1299 cell lines expressing low levels of p53 specifically targeted to the matrix. Using immunoprecipitation and mass spectrometry, we identified the oligomycin sensitivity-conferring protein (oSCP), a subunit of the F1F0-atP synthase complex, as a new partner of endogenous p53, specifically interacting with p53 localized in the matrix. Interestingly, this interaction seems implicated in mitochondrial p53 localization. Moreover, p53 localized in the matrix promotes the assembly of F1F0-atP synthase. taking into account that deregulations of mitochondrial respiration and reactive oxygen species production are tightly linked to cancer development, we suggest that mitochondrial p53 may be an important regulator of normal mitochondrial and cellular physiology, potentially exerting tumor suppression activity inside mitochondria.

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The Import of the Transcription Factor STAT3 into Mitochondria Depends on GRIM-19, a Component of the Electron Transport Chain

Cited by 184 publications

References 48 publications

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

Mitoneet mediates TNFα induced necroptosis promoted by fructose and ethanol exposure

The role of STAT3 in autophagy

Mitochondrial p53 mediates a transcription-independent regulation of cell respiration and interacts with the mitochondrial F₁F₀-ATP synthase

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