The 55-kDa Tumor Necrosis Factor Receptor Induces Clustering of Mitochondria through Its Membrane-proximal Region

Abstract

The cytokine tumor necrosis factor (TNF) activates diverse signaling molecules resulting in gene expression, differentiation, and/or cell death. Here we report a novel feature induced by TNF, namely translocation of mitochondria from a dispersed distribution to a perinuclear cluster. Mitochondrial translocation correlated with sensitivity to the cell death-inducing activity of TNF and was mediated by the 55-kDa TNF receptor (TNF-R55), but not by Fas, indicating that the signaling pathway requires a TNF-R55-specific but death domain-independent signal. Indeed, using L929 cells that express mutant TNF-R55, we showed that the membrane-proximal region of TNF-R55 was essential for signaling to mitochondrial translocation. In the absence of translocation, the cell death response was markedly delayed, pointing to a cooperative effect on cell death. Translocation of mitochondria, although dependent on the microtubules, was not imposed by the latter and was equally induced by TNF-independent immunoinhibition of the motor protein kinesin. Additionally, immunoinhibition with antibody directed against the tail domain of kinesin synergized with TNF-induced cell death. Based on this functional mimicry, we propose that a TNF-R55 membrane-proximal region-dependent signal impedes mitochondria-associated kinesin, resulting in cooperation with the TNF-R55 death domain-induced cytotoxic response and causing the observed clustering of mitochondria. The cytokine tumor necrosis factor (TNF) activates diverse signaling molecules resulting in gene expression, differentiation, and/or cell death. Here we report a novel feature induced by TNF, namely translocation of mitochondria from a dispersed distribution to a perinuclear cluster. Mitochondrial translocation correlated with sensitivity to the cell death-inducing activity of TNF and was mediated by the 55-kDa TNF receptor (TNF-R55), but not by Fas, indicating that the signaling pathway requires a TNF-R55-specific but death domain-independent signal. Indeed, using L929 cells that express mutant TNF-R55, we showed that the membrane-proximal region of TNF-R55 was essential for signaling to mitochondrial translocation. In the absence of translocation, the cell death response was markedly delayed, pointing to a cooperative effect on cell death. Translocation of mitochondria, although dependent on the microtubules, was not imposed by the latter and was equally induced by TNF-independent immunoinhibition of the motor protein kinesin. Additionally, immunoinhibition with antibody directed against the tail domain of kinesin synergized with TNF-induced cell death. Based on this functional mimicry, we propose that a TNF-R55 membrane-proximal region-dependent signal impedes mitochondria-associated kinesin, resulting in cooperation with the TNF-R55 death domain-induced cytotoxic response and causing the observed clustering of mitochondria. Mitochondria are the energy-providing organelles in eukaryotic cells. However, accumulating evidence shows that these organelles also have an active function in cell death. Disruption of mitochondrial transmembrane potential (ΔΨm) 1The abbreviations used are: ΔΨm, mitochondrial transmembrane potential; Ab, antibody; CHX, cycloheximide; CLSM, confocal laser scanning microscopy; DD, death domain; FITC, fluorescein isothiocyanate; hTNF, human TNF; IL-6, interleukin-6; KHC, kinesin heavy chain; mAb, monoclonal antibody; MT, microtubule; mTNF, murine TNF; NF-κB, nuclear factor κB; PI, propidium iodide; R123, rhodamine 123; ROS, reactive oxygen species; TNF, tumor necrosis factor; TNF-R55, 55-kDa TNF receptor; TNF-R75, 75-kDa TNF receptor; MEM, minimal essential medium; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. 1The abbreviations used are: ΔΨm, mitochondrial transmembrane potential; Ab, antibody; CHX, cycloheximide; CLSM, confocal laser scanning microscopy; DD, death domain; FITC, fluorescein isothiocyanate; hTNF, human TNF; IL-6, interleukin-6; KHC, kinesin heavy chain; mAb, monoclonal antibody; MT, microtubule; mTNF, murine TNF; NF-κB, nuclear factor κB; PI, propidium iodide; R123, rhodamine 123; ROS, reactive oxygen species; TNF, tumor necrosis factor; TNF-R55, 55-kDa TNF receptor; TNF-R75, 75-kDa TNF receptor; MEM, minimal essential medium; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. during apoptosis induced by various stimuli in diverse cell types represents an irreversible commitment to cell death, preceding the late characteristics of apoptosis, such as DNA condensation and degradation as well as formation of apoptotic bodies (1Zamzami N. Marchetti P. Castedo M. Zanin C. Vayssière J.-L. Petit P.X. Kroemer G. J. Exp. Med. 1995; 181: 1661-1672Crossref PubMed Scopus (1092) Google Scholar, 2Marchetti P. Castedo M. Susin S.A. Zamzami N. Hirsch T. Macho A. Haeffner A. Hirsch F. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1155-1160Crossref PubMed Scopus (780) Google Scholar). A causative link between ΔΨm and nuclear apoptosis is supported by the release of a caspase-like, apoptosis-inducing factor from the mitochondrial intermembrane space after permeability transition, a condition leading to ΔΨm disruption (3Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar). In addition to apoptosis-inducing factor, cytochrome c induces apoptosis in a cell-free system in the presence of dATP and cytosolic extracts (4Liu X. Kim C.N. Yang J. Jemmerson R. Wang X. 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Liu X. Bhalla K. Kim C.N. Ibrado A.M. Cai J. Peng T.-I. Jones D.P. Wang X. Science. 1997; 275: 1129-1132Crossref PubMed Scopus (4397) Google Scholar), and Bcl-xLinhibits the accumulation of cytochrome c in the cytosol during apoptosis possibly by binding to it and thus blocking its availability (7Kharbanda S. Pandey P. Schofield L. Israels S. Roncinske R. Yoshida K. Bharti A. Yuan Z.-M. Saxena S. Weichselbaum R. Nalin C. Kufe D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 6939-6942Crossref PubMed Scopus (368) Google Scholar). Therefore, the antiapoptotic role of Bcl-2 and family members could be based on counteracting mitochondrial dysfunction and subsequent release of apoptogenic factors. Mitochondrial dysfunction also plays a crucial role in cell types that exhibit necrosis-like cell death after activation of their death program. Disruption of plasma membrane integrity by the proinflammatory cytokine tumor necrosis factor (TNF) represents an irreversible commitment to cell death in the murine fibrosarcoma cell line L929 (8Grooten J. Goossens V. Vanhaesebroeck B. Fiers W. Cytokine. 1993; 5: 546-555Crossref PubMed Scopus (87) Google Scholar) and depends on the production of reactive oxygen species (ROS) by the mitochondria (9Schulze-Osthoff K. Bakker A.C. Vanhaesebroeck B. Beyaert R. Jacob W.A. Fiers W. J. Biol. Chem. 1992; 267: 5317-5323Abstract Full Text PDF PubMed Google Scholar, 10Schulze-Osthoff K. Beyaert R. Vandevoorde V. Haegeman G. Fiers W. EMBO J. 1993; 12: 3095-3104Crossref PubMed Scopus (548) Google Scholar, 11Goossens V. Grooten J. De Vos K. Fiers W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8115-8119Crossref PubMed Scopus (555) Google Scholar). Also, in drug-resistant leukemia cells, inhibition of the mitochondrial respiratory chain by TNF is, at least partially, responsible for cytotoxicity (12Jia L. Kelsey S.M. Grahn M.F. Jiang X.R. Newland A.C. Blood. 1996; 87: 2401-2410Crossref PubMed Google Scholar), while in human ovarian carcinoma cell lines there is evidence for an involvement of mitochondrial ROS in TNF-mediated cell death (13Uslu R. Bonavida B. Cancer. 1996; 77: 725-732Crossref PubMed Scopus (47) Google Scholar). The 55-kDa TNF receptor (TNF-R55) and Fas (APO-1 or CD95), both members of the TNF receptor family, can trigger the cell death program of several cell types. Additionally, TNF-R55 mediates gene induction by activation of the nuclear factor κB (NF-κB) and the transcription factors AP-1 and ATF-2 (14Beyaert R. Fiers W. 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Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In this we a novel activity of TNF, namely the induction of an distribution of mitochondria in cells. translocation of mitochondria depends on a signal from the membrane-proximal region of TNF-R55 and thus represents a novel function of this The of this translocation was not the but a of directed of mitochondria by an activity of the motor kinesin. as well as the of mitochondrial translocation and its with the death-inducing activity of TNF, but not with gene this response and its namely of mitochondria-associated kinesin, in the cell death and cells B. S. A. P. Beyaert R. R. F. Fiers W. Google Scholar) and E. in with and at in a human cells in with and and S.A. J. Biol. PubMed Scopus Google Scholar) from the by the of and of and the of of from the of in as cell lines as from an TNF was and to at least in a activity of of protein for and of of and was used at and from used at of and and from used at of was used at antibody and by of a from and with was using an from to the in and at in a Mitochondria with or for at L929 cells and cells with MEM, with the as to or and in was of the and the by cells in during the The distribution of mitochondria was with a confocal and and as in The at TNF was is to as after TNF confocal laser scanning from cells, Translocation was as the of cells the mitochondrial of in a induced by TNF and Fas in cells was in a based on DNA degradation using in a the of with the of In cells, this in to the and of the cell by apoptosis resulting in and cells by in the presence of The of cells was with an using the and as in as a for TNF-induced death of L929 and cell lines was by of cells by and was induced by with TNF in TNF and in a of M. F. or in and and Fas in cells. death is as the of cells in the cell was to at the as at and on an resulting from was and cells and The observed in ROS was The presence of in the of was after of TNF using the response of the murine cell line J. S. A. C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). L929 cells on was to the for to mitochondria at with for by with at for by with and a with of the kinesin heavy chain was by of with in observed with a confocal with a scanning of and line The and used for the are in of L929 cells with was as J. Sci. 1992; Google Scholar). L929 cells from by with cell cells to a in a of of was to a of with an of by the addition of was a and and the cells in for The cells to for the was cell death resulting from cells by after the cells by the presence of in the cytosol and of the cell and cells from by with cell cells for with the a of M. in the of or or from used as was on an of was in an of cells with TNF for protein and binding as Haegeman G. Vandevoorde V. Fiers W. 1993; PubMed Scopus Google Scholar). L929 cells in and various and of protein was on a to a membrane by and for Ab, mAb, or was used at TNF of the murine fibrosarcoma cell line L929 in cell death by an necrosis-like is by cell disruption of plasma membrane and (8Grooten J. Goossens V. Vanhaesebroeck B. Fiers W. Cytokine. 1993; 5: 546-555Crossref PubMed Scopus (87) Google Scholar). Mitochondrial dysfunction is crucial in this TNF-induced cytotoxic ROS are in the mitochondria, and with the or of these ROS cell death (9Schulze-Osthoff K. Bakker A.C. Vanhaesebroeck B. Beyaert R. Jacob W.A. Fiers W. J. Biol. Chem. 1992; 267: 5317-5323Abstract Full Text PDF PubMed Google Scholar, 10Schulze-Osthoff K. Beyaert R. Vandevoorde V. Haegeman G. Fiers W. EMBO J. 1993; 12: 3095-3104Crossref PubMed Scopus (548) Google Scholar, 11Goossens V. Grooten J. De Vos K. Fiers W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8115-8119Crossref PubMed Scopus (555) Google Scholar). CLSM, we observed that of of L929 cells with TNF the distribution of mitochondria in the of the cells from an or distribution to an distribution of the of this mitochondrial translocation that the response mitochondrial ROS production and subsequent cell death by several these the was that this not with cell or to However, the of from its accumulation in the mitochondria, a disruption of a of the mitochondria could be as a translocation. the distribution of mitochondria with a that is in the mitochondria by the of its A. D. Castedo M. Hirsch T. Susin S.A. Zamzami N. Kroemer G. 1996; PubMed Scopus Google Scholar), an distribution to the observed after with TNF not the distribution of and in L929 cells the distribution of mitochondria and not a of ΔΨm in a of the translocation of mitochondria cell death. the of cells mitochondria of cells and of ROS production was the addition of Translocation was by in cells using the death was by The production of mitochondrial ROS was in a as V. Grooten J. De Vos K. Fiers W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8115-8119Crossref PubMed Scopus (555) Google Scholar) using the and is as the in to cells. The are of cells. to L929 cells, TNF-induced translocation of mitochondria was by The of cells was by based on the of cells cell death was induced in L929 cells by with TNF or the cytotoxic or of the of mitochondrial translocation and cell death was as In to cell death induced by TNF in the human cell line is by plasma membrane DNA and subsequent formation of apoptotic bodies not of also in these cells mitochondria in response to with TNF, cells with and by in cells a distribution of mitochondria of TNF preceding the of the apoptotic response by several translocation of mitochondria of the of cell death, necrosis-like or and is an feature to the of the cell death program. death is by that of the of signal the the observed translocation of mitochondria could be such a we induced cell death in L929 cells by of the cytotoxic or after the distribution of mitochondria was in the distribution of mitochondria that induction of mitochondrial translocation is an feature of the TNF signal the between the observed clustering of mitochondria and the of TNF, we the of mitochondrial translocation, cell death, activation of NF-κB, and gene induction in the L929 B. S. A. P. Beyaert R. R. F. Fiers W. Google Scholar). cells are to the activity of TNF but to its by activation of and subsequent of However, the addition of the or protein or CHX, the response to in mitochondria after TNF in the presence of at a to that observed in the L929 cell However, in the absence of CHX, mitochondrial translocation not the activation by TNF of and gene between translocation and cell death, but not gene expression, that the TNF-induced clustering of mitochondria is to the cell death-inducing activity of the In L929 cells, mitochondrial translocation was to the by and not However, the latter to TNF-R55 but not to M. Lee A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), indicating that translocation is a the TNF-R55 is and to cell death V. Haegeman G. Fiers W. J. Biol. 1997; PubMed Scopus Google Scholar, D. J. Biol. 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In the cells by TNF showed translocation of mitochondria cell death. the induction of mitochondrial translocation is a feature for TNF-R55 and not by the membrane-proximal region of TNF-R55 in Fas, we its involvement in the of the translocation signal with L929 and The the the latter the mutant the membrane-proximal region to Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). that of by the in clustering of mitochondria and cell death. with induced by by mAb, to the of the receptor However, the not clustering of mitochondria of was not to clustering of the the translocation of mitochondria. this induction of clustering was by a in the of cell death, the of the receptor and using not Also, the absence of mitochondrial translocation and the cell death after clustering of was not by a activity as by the of and activation of p38/RK mitogen-activated protein kinase not the TNF-R55 membrane-proximal region is to the signal for translocation as well as to the Mitochondria and organelles are with the the the of the organelles in the The transition of mitochondrial distribution in cells from an to a perinuclear thus be a of a transition of the was supported by the that the clustering of mitochondria of the and the distribution of mitochondria, that an system is for this In with F. E. J. Exp. Med. PubMed Scopus Google Scholar), disruption of the also in TNF receptor not it to the effect of on TNF-induced cell death. In to the not TNF-induced mitochondrial translocation or cell death and not the effect of prevents of the this it that such a is responsible for the observed clustering of mitochondria. was supported by of the in with mitochondria in and cells the to the plasma membrane in both and cells, while in cells the mitochondria are the cell but have to the perinuclear Therefore, a of the can be as the the TNF-induced translocation of mitochondria. the effect of that the of mitochondrial translocation requires The distribution of mitochondria, as well as of is directed not by the of the but also by the of the organelles the by such as kinesin PubMed Scopus Google Scholar, Cell. Full Text PDF PubMed Scopus Google Scholar) and Cell. Full Text PDF PubMed Scopus Google Scholar). 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EMBO J. 1993; 12: 3095-3104Crossref PubMed Scopus (548) Google Scholar, 11Goossens V. Grooten J. De Vos K. Fiers W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8115-8119Crossref PubMed Scopus (555) Google Scholar). Here we report that TNF induces a of the distribution of from an or distribution in cells to a the in cells. clustering was induced by TNF and correlated with the death-inducing activity of the of the of the cell death apoptotic or this distribution of mitochondria in response to TNF represents a novel activity of the cytokine in cells. The of TNF-induced clustering of mitochondria with cell death that TNF-R55 and not mediates this Indeed, of TNF-R55 by hTNF, is a TNF-R55-specific for murine cells M. Lee A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), induced translocation of mitochondria in L929 cells. The of both TNF-R55 and Fas is to be the of the cell death signal of these death However, mitochondrial translocation was observed during cell death, suggesting that the signal is TNF-R55 L929 cells mutant TNF-R55, we showed that the membrane-proximal domain of this receptor is essential for signaling to mitochondrial translocation. a function to the membrane-proximal namely induction of translocation of mitochondria to the perinuclear and the induction of the response by TNF-R55 but not by we that in the absence of the membrane-proximal domain also the cell death response was markedly a cooperative effect on the response of the signal from the membrane-proximal of the of the TNF-R55 membrane-proximal induction of and to be in the signal leading to cell death. the is in the mutant and TNF not in L929 cells, both signaling can be as not of the cell activity of the membrane-proximal region but also of its mitochondrial be that both on signaling the of translocation with cell death, these be functional on the TNF-R55 membrane-proximal region be to the signaling and we showed that are for translocation, although the not an distribution of mitochondria. to a motor Indeed, we that immunoinhibition of kinesin in a translocation to that observed by after TNF TNF to of mitochondria. be mediated by that are to be during TNF-induced However, in L929 cells activation is in these cells the not mitochondrial translocation not the of an involvement of in this are such as and the of organelles after 1993; PubMed Scopus Google Scholar, J. 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