The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Teresa Mampel - One of the best experts on this subject based on the ideXlab platform.

  • changes in the expression of the human Adenine Nucleotide Translocase isoforms condition cellular metabolic proliferative status
    Open Biology, 2016
    Co-Authors: Aleix Gavaldanavarro, Teresa Mampel, Octavi Vinas
    Abstract:

    Human cells express four mitochondrial Adenine Nucleotide Translocase (hANT) isoforms that are tissue-specific and developmentally regulated. hANT1 is mainly expressed in terminally differentiated muscle cells; hANT2 is growth-regulated and is upregulated in highly glycolytic and proliferative cells; and hANT3 is considered to be ubiquitous and non-specifically regulated. Here, we studied how the expression of hANT isoforms is regulated by proliferation and in response to metabolic stimuli, and examined the metabolic consequences of their silencing and overexpression. In HeLa and HepG2 cells, expression of hANT3 was upregulated by shifting metabolism towards oxidation or by slowed growth associated with contact inhibition or growth-factor deprivation, indicating that hANT3 expression is highly regulated. Under these conditions, changes in hANT2 mRNA expression were not observed in either HeLa or HepG2 cells, whereas in SGBS preadipocytes (which, unlike HeLa and HepG2 cells, are growth-arrest-sensitive cells), hANT2 mRNA levels decreased. Additionally, overexpression of hANT2 promoted cell growth and glycolysis, whereas silencing of hANT3 decreased cellular ATP levels, limited cell growth and induced a stress-like response. Thus, cancer cells require both hANT2 and hANT3, depending on their proliferation status: hANT2 when proliferation rates are high, and hANT3 when proliferation slows.

  • expression of Adenine Nucleotide Translocase ant isoform genes is controlled by pgc 1α through different transcription factors
    Journal of Cellular Physiology, 2014
    Co-Authors: Aleix Gavaldanavarro, Octavi Vinas, Josep A Villena, Anna Planavila, Teresa Mampel
    Abstract:

    Adenine Nucleotide Translocase (ANT) isoforms are mitochondrial proteins encoded by nuclear DNA that catalyze the exchange of ATP generated in the mitochondria for ADP produced in the cytosol. The aim of this study was to determine the role of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor-γ [PPAR-γ] coactivator 1α), a master regulator of mitochondrial oxidative metabolism, in the regulation of the expression of ANT isoform genes and to identify the transcription factors involved. We found that PGC-1α overexpression induced the expression of all ANT human and mouse isoforms but to different degrees. The transcription factor ERRα was involved in PGC-1α-induced expression of all human ANT isoforms (hANT1-3) in HeLa cells as well as in the regulation of mouse isoforms (mANT1-2) in C2C12 myotubes and 3T3-L1 adipocytes, even though ANT isoforms have important physiological differences and are regulated in a tissue-specific manner. In addition to ERRα, PPARδ and mTOR pathways were involved in the induction of mANT1-2 by PGC-1α in C2C12 myotubes, while PPARγ was involved in PGC-1α-regulation of mANT1-2 in 3T3-L1 adipocytes. Furthermore, the regulation of mANT genes by PGC-1α was also observed in vivo in knockout mouse models lacking PGC-1α. In summary, our results show that the regulation of genes encoding ANT isoforms is controlled by PGC-1α through different transcription factors depending on cell type.

  • recruitment of nf κb into mitochondria is involved in Adenine Nucleotide Translocase 1 ant1 induced apoptosis
    Journal of Biological Chemistry, 2004
    Co-Authors: Monica Zamora, Octavi Vinas, Claudia Merono, Teresa Mampel
    Abstract:

    Overexpression of Adenine Nucleotide Translocase-1 (ANT1) is known to induce apoptosis (Bauer, M. K., Schubert, A., Rocks, O., and Grimm, S. (1999) J. Cell Biol. 147, 1493–1501), but the mechanisms involved remain unclear. In this study we show that ANT1 overexpression results in a recruitment of the IκBα-NF-κB complex into mitochondria, with a coincident decrease in nuclear NF-κB DNA binding activity. In this situation, NF-κB transcriptionally regulated genes with antiapoptotic activity, such as Bcl-XL, MnSOD2, and c-IAP2, are down-regulated, and consequently, cells are sensitized to apoptosis. Accordingly, co-expression of p65 partially interferes with the proapoptotic effect of ANT1 overexpression. Despite the high identity of the two isoforms, overexpression of ANT2 does not exert an apoptotic effect; this lack of apoptotic activity is correlated with the absence of mitochondrial IκBα-NF-κB recruitment or changes in NF-κB activity. Thus, we propose that the mitochondrial recruitment of NF-κB observed following ANT1 overexpression has an important role in ANT1 proapoptotic activity.

  • Adenine Nucleotide Translocase 3 ant3 overexpression induces apoptosis in cultured cells
    FEBS Letters, 2004
    Co-Authors: Monica Zamora, Meritxell Granell, Teresa Mampel, Octavi Vinas
    Abstract:

    Mitochondrial Adenine Nucleotide Translocase 1 (ANT1), but not ANT2, can dominantly induce apoptosis. Nothing is known, however, about the apoptotic activity of ANT3. We have transfected HeLa cells with the three human ANT isoforms to compare their potential as inducers of apoptosis. Transient overexpression of ANT3 resulted, like ANT1, in apoptosis as shown by an increase in the sub-G1 fraction, annexin V staining, low DeltaPsi(m), and activation of caspases 9 and 3. Moreover, the apoptosis produced by ANT3 was inhibited by bongkrekic acid and by cyclosporin A. The pro-apoptotic activities of the ANT1 and ANT3 isoforms contrast with the lack of apoptotic activity of ANT2. This finding may help to identify the specific factors associated with the pro-apoptotic activities of ANT isoforms.

  • all trans retinoic acid binds to and inhibits Adenine Nucleotide Translocase and induces mitochondrial permeability transition
    Molecular Pharmacology, 2003
    Co-Authors: Belen Notario, Monica Zamora, Octavi Vinas, Teresa Mampel
    Abstract:

    We investigated the effects of retinoic acids on mitochondrial permeability transition (MPT) measured as changes in rhodamine 123 fluorescence from both isolated heart mitochondria and HeLa cells. We report that all- trans -retinoic acid (atRA), 9- cis -retinoic acid, and 13- cis -retinoic acid induce a drop in mitochondrial membrane potential in isolated mitochondria. The atRA effect was done through the induction of MPT because it was dependent on Ca2+, in a synergic mechanism, and inhibited by cyclosporin A (CsA). Furthermore, atRA also opened MPT in vivo, because treatment of HeLa cells with atRA results in a CsA-sensitive drop of mitochondrial membrane potential. We demonstrated for the first time that retinoic acids inhibit Adenine Nucleotide Translocase (ANT) activity in heart and liver mitochondria. Kinetic studies revealed atRA as an uncompetitive inhibitor of ANT. Photoaffinity labeling of mitochondrial proteins with [3H]atRA demonstrated the binding of a 31-kDa protein to atRA. This protein was identified as ANT because the presence of carboxyatractyloside, a specific ANT inhibitor, prevented labeling. The specific photolabeling of ANT was also prevented in a concentration-dependent manner by nonlabeled atRA, whereas palmitic acid was ineffective. This study indicates that specific interaction between atRA and ANT takes place regulating MPT opening and adenylate transport. These observations establish a novel mechanism for atRA action, which could control both energetic and apoptotic mitochondrial processes in situations such as retinoic acid treatment.

Octavi Vinas - One of the best experts on this subject based on the ideXlab platform.

  • changes in the expression of the human Adenine Nucleotide Translocase isoforms condition cellular metabolic proliferative status
    Open Biology, 2016
    Co-Authors: Aleix Gavaldanavarro, Teresa Mampel, Octavi Vinas
    Abstract:

    Human cells express four mitochondrial Adenine Nucleotide Translocase (hANT) isoforms that are tissue-specific and developmentally regulated. hANT1 is mainly expressed in terminally differentiated muscle cells; hANT2 is growth-regulated and is upregulated in highly glycolytic and proliferative cells; and hANT3 is considered to be ubiquitous and non-specifically regulated. Here, we studied how the expression of hANT isoforms is regulated by proliferation and in response to metabolic stimuli, and examined the metabolic consequences of their silencing and overexpression. In HeLa and HepG2 cells, expression of hANT3 was upregulated by shifting metabolism towards oxidation or by slowed growth associated with contact inhibition or growth-factor deprivation, indicating that hANT3 expression is highly regulated. Under these conditions, changes in hANT2 mRNA expression were not observed in either HeLa or HepG2 cells, whereas in SGBS preadipocytes (which, unlike HeLa and HepG2 cells, are growth-arrest-sensitive cells), hANT2 mRNA levels decreased. Additionally, overexpression of hANT2 promoted cell growth and glycolysis, whereas silencing of hANT3 decreased cellular ATP levels, limited cell growth and induced a stress-like response. Thus, cancer cells require both hANT2 and hANT3, depending on their proliferation status: hANT2 when proliferation rates are high, and hANT3 when proliferation slows.

  • expression of Adenine Nucleotide Translocase ant isoform genes is controlled by pgc 1α through different transcription factors
    Journal of Cellular Physiology, 2014
    Co-Authors: Aleix Gavaldanavarro, Octavi Vinas, Josep A Villena, Anna Planavila, Teresa Mampel
    Abstract:

    Adenine Nucleotide Translocase (ANT) isoforms are mitochondrial proteins encoded by nuclear DNA that catalyze the exchange of ATP generated in the mitochondria for ADP produced in the cytosol. The aim of this study was to determine the role of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor-γ [PPAR-γ] coactivator 1α), a master regulator of mitochondrial oxidative metabolism, in the regulation of the expression of ANT isoform genes and to identify the transcription factors involved. We found that PGC-1α overexpression induced the expression of all ANT human and mouse isoforms but to different degrees. The transcription factor ERRα was involved in PGC-1α-induced expression of all human ANT isoforms (hANT1-3) in HeLa cells as well as in the regulation of mouse isoforms (mANT1-2) in C2C12 myotubes and 3T3-L1 adipocytes, even though ANT isoforms have important physiological differences and are regulated in a tissue-specific manner. In addition to ERRα, PPARδ and mTOR pathways were involved in the induction of mANT1-2 by PGC-1α in C2C12 myotubes, while PPARγ was involved in PGC-1α-regulation of mANT1-2 in 3T3-L1 adipocytes. Furthermore, the regulation of mANT genes by PGC-1α was also observed in vivo in knockout mouse models lacking PGC-1α. In summary, our results show that the regulation of genes encoding ANT isoforms is controlled by PGC-1α through different transcription factors depending on cell type.

  • recruitment of nf κb into mitochondria is involved in Adenine Nucleotide Translocase 1 ant1 induced apoptosis
    Journal of Biological Chemistry, 2004
    Co-Authors: Monica Zamora, Octavi Vinas, Claudia Merono, Teresa Mampel
    Abstract:

    Overexpression of Adenine Nucleotide Translocase-1 (ANT1) is known to induce apoptosis (Bauer, M. K., Schubert, A., Rocks, O., and Grimm, S. (1999) J. Cell Biol. 147, 1493–1501), but the mechanisms involved remain unclear. In this study we show that ANT1 overexpression results in a recruitment of the IκBα-NF-κB complex into mitochondria, with a coincident decrease in nuclear NF-κB DNA binding activity. In this situation, NF-κB transcriptionally regulated genes with antiapoptotic activity, such as Bcl-XL, MnSOD2, and c-IAP2, are down-regulated, and consequently, cells are sensitized to apoptosis. Accordingly, co-expression of p65 partially interferes with the proapoptotic effect of ANT1 overexpression. Despite the high identity of the two isoforms, overexpression of ANT2 does not exert an apoptotic effect; this lack of apoptotic activity is correlated with the absence of mitochondrial IκBα-NF-κB recruitment or changes in NF-κB activity. Thus, we propose that the mitochondrial recruitment of NF-κB observed following ANT1 overexpression has an important role in ANT1 proapoptotic activity.

  • Adenine Nucleotide Translocase 3 ant3 overexpression induces apoptosis in cultured cells
    FEBS Letters, 2004
    Co-Authors: Monica Zamora, Meritxell Granell, Teresa Mampel, Octavi Vinas
    Abstract:

    Mitochondrial Adenine Nucleotide Translocase 1 (ANT1), but not ANT2, can dominantly induce apoptosis. Nothing is known, however, about the apoptotic activity of ANT3. We have transfected HeLa cells with the three human ANT isoforms to compare their potential as inducers of apoptosis. Transient overexpression of ANT3 resulted, like ANT1, in apoptosis as shown by an increase in the sub-G1 fraction, annexin V staining, low DeltaPsi(m), and activation of caspases 9 and 3. Moreover, the apoptosis produced by ANT3 was inhibited by bongkrekic acid and by cyclosporin A. The pro-apoptotic activities of the ANT1 and ANT3 isoforms contrast with the lack of apoptotic activity of ANT2. This finding may help to identify the specific factors associated with the pro-apoptotic activities of ANT isoforms.

  • all trans retinoic acid binds to and inhibits Adenine Nucleotide Translocase and induces mitochondrial permeability transition
    Molecular Pharmacology, 2003
    Co-Authors: Belen Notario, Monica Zamora, Octavi Vinas, Teresa Mampel
    Abstract:

    We investigated the effects of retinoic acids on mitochondrial permeability transition (MPT) measured as changes in rhodamine 123 fluorescence from both isolated heart mitochondria and HeLa cells. We report that all- trans -retinoic acid (atRA), 9- cis -retinoic acid, and 13- cis -retinoic acid induce a drop in mitochondrial membrane potential in isolated mitochondria. The atRA effect was done through the induction of MPT because it was dependent on Ca2+, in a synergic mechanism, and inhibited by cyclosporin A (CsA). Furthermore, atRA also opened MPT in vivo, because treatment of HeLa cells with atRA results in a CsA-sensitive drop of mitochondrial membrane potential. We demonstrated for the first time that retinoic acids inhibit Adenine Nucleotide Translocase (ANT) activity in heart and liver mitochondria. Kinetic studies revealed atRA as an uncompetitive inhibitor of ANT. Photoaffinity labeling of mitochondrial proteins with [3H]atRA demonstrated the binding of a 31-kDa protein to atRA. This protein was identified as ANT because the presence of carboxyatractyloside, a specific ANT inhibitor, prevented labeling. The specific photolabeling of ANT was also prevented in a concentration-dependent manner by nonlabeled atRA, whereas palmitic acid was ineffective. This study indicates that specific interaction between atRA and ANT takes place regulating MPT opening and adenylate transport. These observations establish a novel mechanism for atRA action, which could control both energetic and apoptotic mitochondrial processes in situations such as retinoic acid treatment.

Nilserik L Saris - One of the best experts on this subject based on the ideXlab platform.

  • to involvement the conformation of the Adenine Nucleotide Translocase in opening the tl induced permeability transition pore in ca2 loaded rat liver mitochondria
    Toxicology in Vitro, 2016
    Co-Authors: S M Korotkov, Svetlana A Konovalova, Irina V Brailovskaya, Nilserik L Saris
    Abstract:

    The conformation of Adenine Nucleotide Translocase (ANT) has a profound impact in opening the mitochondrial permeability transition pore (MPTP) in the inner membrane. Fixing the ANT in 'c' conformation by phenylarsine oxide (PAO), tert-butylhydroperoxide (tBHP), and carboxyatractyloside as well as the interaction of 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) with mitochondrial thiols markedly attenuated the ability of ADP to inhibit the MPTP opening. We earlier found (Korotkov and Saris, 2011) that calcium load of rat liver mitochondria in medium containing TlNO3 and KNO3 stimulated the Tl(+)-induced MPTP opening in the inner mitochondrial membrane. The MPTP opening as well as followed increase in swelling, a drop in membrane potential (ΔΨmito), and a decrease in state 3, state 4, and 2,4-dinitrophenol-uncoupled respiration were visibly enhanced in the presence of PAO, tBHP, DIDS, and carboxyatractyloside. However, these effects were markedly inhibited by ADP and membrane-penetrant hydrophobic thiol reagent, N-ethylmaleimide (NEM) which fix the ANT in 'm' conformation. Cyclosporine A additionally potentiated these effects of ADP and NEM. Our data suggest that conformational changes of the ANT may be directly involved in the opening of the Tl(+)-induced MPTP in the inner membrane of Ca(2+)-loaded rat liver mitochondria. Using the Tl(+)-induced MPTP model is discussed in terms finding new transition pore inhibitors and inducers among different chemical and natural compounds.

  • Adenine Nucleotide Translocase mediates the katp channel openers induced proton and potassium flux to the mitochondrial matrix
    Journal of Bioenergetics and Biomembranes, 2003
    Co-Authors: Dalia M Kopustinskiene, Adolfas Toleikis, Nilserik L Saris
    Abstract:

    KATP channel openers have been shown to protect ischemic-reperfused myocardium by mimicking ischemic preconditioning, although their mechanisms of action have not been fully clarified. In this study we investigated the influence of the Adenine Nucleotide Translocase (ANT) inhibitors–carboxyatractyloside (CAT) and bongkrekic acid (BA)–on the diazoxide- and pinacidil-induced uncoupling of isolated rat heart mitochondria respiring on pyruvate and malate (6 + 6 mM). We found that both CAT (1.3 μM) and BA (20 μM) markedly reduced the uncoupling of mitochondrial oxidative phosphorylation induced by the KATP channel openers. Thus, the uncoupling effect of diazoxide and pinacidil is evident only when ANT is not fixed by inhibitors in neither the C- nor the M-conformation. Moreover, the uncoupling effect of diazoxide and pinacidil was diminished in the presence of ADP or ATP, indicating a competition of KATP channel openers with Adenine Nucleotides. CAT also abolished K+-dependent mitochondrial respiratory changes. Thus ANT could also be involved in the regulation of KATP-channel-openers-induced K+ flux through the inner mitochondrial membrane.

Monica Zamora - One of the best experts on this subject based on the ideXlab platform.

  • recruitment of nf κb into mitochondria is involved in Adenine Nucleotide Translocase 1 ant1 induced apoptosis
    Journal of Biological Chemistry, 2004
    Co-Authors: Monica Zamora, Octavi Vinas, Claudia Merono, Teresa Mampel
    Abstract:

    Overexpression of Adenine Nucleotide Translocase-1 (ANT1) is known to induce apoptosis (Bauer, M. K., Schubert, A., Rocks, O., and Grimm, S. (1999) J. Cell Biol. 147, 1493–1501), but the mechanisms involved remain unclear. In this study we show that ANT1 overexpression results in a recruitment of the IκBα-NF-κB complex into mitochondria, with a coincident decrease in nuclear NF-κB DNA binding activity. In this situation, NF-κB transcriptionally regulated genes with antiapoptotic activity, such as Bcl-XL, MnSOD2, and c-IAP2, are down-regulated, and consequently, cells are sensitized to apoptosis. Accordingly, co-expression of p65 partially interferes with the proapoptotic effect of ANT1 overexpression. Despite the high identity of the two isoforms, overexpression of ANT2 does not exert an apoptotic effect; this lack of apoptotic activity is correlated with the absence of mitochondrial IκBα-NF-κB recruitment or changes in NF-κB activity. Thus, we propose that the mitochondrial recruitment of NF-κB observed following ANT1 overexpression has an important role in ANT1 proapoptotic activity.

  • Adenine Nucleotide Translocase 3 ant3 overexpression induces apoptosis in cultured cells
    FEBS Letters, 2004
    Co-Authors: Monica Zamora, Meritxell Granell, Teresa Mampel, Octavi Vinas
    Abstract:

    Mitochondrial Adenine Nucleotide Translocase 1 (ANT1), but not ANT2, can dominantly induce apoptosis. Nothing is known, however, about the apoptotic activity of ANT3. We have transfected HeLa cells with the three human ANT isoforms to compare their potential as inducers of apoptosis. Transient overexpression of ANT3 resulted, like ANT1, in apoptosis as shown by an increase in the sub-G1 fraction, annexin V staining, low DeltaPsi(m), and activation of caspases 9 and 3. Moreover, the apoptosis produced by ANT3 was inhibited by bongkrekic acid and by cyclosporin A. The pro-apoptotic activities of the ANT1 and ANT3 isoforms contrast with the lack of apoptotic activity of ANT2. This finding may help to identify the specific factors associated with the pro-apoptotic activities of ANT isoforms.

  • all trans retinoic acid binds to and inhibits Adenine Nucleotide Translocase and induces mitochondrial permeability transition
    Molecular Pharmacology, 2003
    Co-Authors: Belen Notario, Monica Zamora, Octavi Vinas, Teresa Mampel
    Abstract:

    We investigated the effects of retinoic acids on mitochondrial permeability transition (MPT) measured as changes in rhodamine 123 fluorescence from both isolated heart mitochondria and HeLa cells. We report that all- trans -retinoic acid (atRA), 9- cis -retinoic acid, and 13- cis -retinoic acid induce a drop in mitochondrial membrane potential in isolated mitochondria. The atRA effect was done through the induction of MPT because it was dependent on Ca2+, in a synergic mechanism, and inhibited by cyclosporin A (CsA). Furthermore, atRA also opened MPT in vivo, because treatment of HeLa cells with atRA results in a CsA-sensitive drop of mitochondrial membrane potential. We demonstrated for the first time that retinoic acids inhibit Adenine Nucleotide Translocase (ANT) activity in heart and liver mitochondria. Kinetic studies revealed atRA as an uncompetitive inhibitor of ANT. Photoaffinity labeling of mitochondrial proteins with [3H]atRA demonstrated the binding of a 31-kDa protein to atRA. This protein was identified as ANT because the presence of carboxyatractyloside, a specific ANT inhibitor, prevented labeling. The specific photolabeling of ANT was also prevented in a concentration-dependent manner by nonlabeled atRA, whereas palmitic acid was ineffective. This study indicates that specific interaction between atRA and ANT takes place regulating MPT opening and adenylate transport. These observations establish a novel mechanism for atRA action, which could control both energetic and apoptotic mitochondrial processes in situations such as retinoic acid treatment.

Andrea Dorner - One of the best experts on this subject based on the ideXlab platform.

  • Adenine Nucleotide Translocase 1 expression modulates the immune response in ischemic hearts
    Cells, 2021
    Co-Authors: Fatih Yergoz, Heinzpeter Schultheiss, Julian Friebel, Nicolle Krankel, Ursula Rauchkroehnert, Ulf Landmesser, Andrea Dorner
    Abstract:

    Adenine Nucleotide Translocase 1 (ANT1) transfers ATP and ADP over the mitochondrial inner membrane and thus supplies the cell with energy. This study analyzed the role of ANT1 in the immune response of ischemic heart tissue. Ischemic ANT1 overexpressing hearts experienced a shift toward an anti-inflammatory immune response. The shift was characterized by low interleukin (IL)-1β expression and M1 macrophage infiltration, whereas M2 macrophage infiltration and levels of IL-10, IL-4, and transforming growth factor (TGFβ) were increased. The modulated immune response correlated with high mitochondrial integrity, reduced oxidative stress, low left ventricular end-diastolic heart pressure, and a high survival rate. Isolated ANT1-transgenic (ANT1-TG) cardiomyocytes expressed low levels of pro-inflammatory cytokines such as IL-1α, tumor necrosis factor α, and TGFβ. However, they showed increased expression and cellular release of anti-inflammatory immunomodulators such as vascular endothelial growth factor. The secretome from ANT1-TG cardiomyocytes initiated stress resistance when applied to ischemic wild-type cardiomyocytes and endothelial cells. It additionally prevented macrophages from expressing pro-inflammatory cytokines. Additionally, ANT1 expression correlated with genes that are related to cytokine and growth factor pathways in hearts of patients with ischemic cardiomyopathy. In conclusion, ANT1-TG cardiomyocytes secrete soluble factors that influence ischemic cardiac cells and initiate an anti-inflammatory immune response in ischemic hearts.

  • transgenic overexpression of Adenine Nucleotide Translocase 1 protects ischemic hearts against oxidative stress
    Journal of Molecular Medicine, 2016
    Co-Authors: Heinzpeter Schultheiss, Ursula Rauch, Ulf Landmesser, Inga Klumpe, Konstantinos Savvatis, Dirk Westermann, Carsten Tschope, Andrea Dorner
    Abstract:

    Ischemia impairs the Adenine Nucleotide Translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia.

  • Adenine Nucleotide Translocase 1 overexpression protects cardiomyocytes against hypoxia via increased erk1 2 and akt activation
    Cellular Signalling, 2016
    Co-Authors: Julia Winter, Heinzpeter Schultheiss, Ursula Rauch, Ulf Landmesser, Inga Klumpe, Jacqueline Heger, Andrea Dorner
    Abstract:

    The influence of mitochondrial function on intracellular signalling is currently under intense investigation. In this regard, we analysed the effect of Adenine Nucleotide Translocase 1 (ANT1), which facilitates the exchange of ADP and ATP across the mitochondrial membrane, on cell-protective survival signalling under hypoxia. ANT1 overexpression enhanced the survival rate in hypoxic cardiomyocytes. The effect was related to stabilization of the mitochondrial membrane potential, suppression of caspase 3 activity, and a reduction in DNA fragmentation. Activation of the cell-protective signalling proteins extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (AKT) was substantially higher in hypoxic ANT1-transgenic (ANT1-TG) cardiomyocytes than in wild-type cardiomyocytes. Kinase activation was associated with significantly higher expression of hypoxia-inducible factor 1α, which induces glycolytic pathway to stabilize ATP production. Accordingly, ANT1-TG cardiomyocytes exhibited earlier and stronger activation of lactate dehydrogenase and a higher ATP content. Treatment with PD980559 and triciribine, inhibitors of ERK1/2 and AKT activation, respectively, abolished cell protection in hypoxic ANT1-TG cardiomyocytes. Inhibition of ANT by carboxyatractyloside prevented the increase in ERK1/2 and AKT phosphorylation and eliminated the cell protective program in hypoxic ANT1-TG cardiomyocytes. In conclusion, the cytoprotective effect observed in hypoxic ANT1-overexpressing cardiomyocytes involves an interdependence between ANT1, activation of ERK1/ERK2 and AKT, and induction of the survival processes regulated by these kinases.

  • transgenic overexpression of heart specific Adenine Nucleotide Translocase 1 positively affects contractile function in cardiomyocytes
    Cellular Physiology and Biochemistry, 2011
    Co-Authors: Inga Vogelpohl, Heinzpeter Schultheiss, Roland Vetter, Jacqueline Heger, Linda Ebermann, Gerhild Euler, Andrea Dorner
    Abstract:

    Background/Aims: The Adenine Nucleotide Translocase (ANT) exchanges ATP and ADP over the inner mitochondrial membrane, supplying the cells with energy. Interestingly, myocardial ANT1 overexpression preserves cardiac structure and function under pathophysiological conditions. To ascertain whether the contractile system is directly affected by increased ANT1 expression, we analyzed cell morphology, contraction and relaxation parameters of ANT1 transgenic (ANT1-TG) cardiomyocytes, myofibrillar protein expression, and Ca2+ handling in ANT1-TG rat hearts. Results: ANT1-TG cardiomyoycytes displayed an elevation in cell volume (52.6±12.0%; p2+ handling, ANT1-TGs revealed a significant elevation in sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) protein level (22.2±4.7%; p2+ uptake into the SR (34%; p2+ ATPase (PMCA) indicated advanced protein expression (23.8±4.8%; p+/Ca2+ exchanger was not altered in ANT1 overexpressing hearts. Conclusion: These data reveal a close association of elevated mitochondrial ATP/ADP transportation via ANT1 with increased contractile function. Furthermore, the ANT1-TGs exhibit an elevation in SR Ca2+ transport that contributes to increased cardiac work, which may protect the heart under pathophysiological conditions.

  • Adenine Nucleotide Translocase in the focus of cardiovascular diseases
    Trends in Cardiovascular Medicine, 2007
    Co-Authors: Andrea Dorner, Heinzpeter Schultheiss
    Abstract:

    Adenine Nucleotide Translocase (ANT) facilitates the exchange of extramitochondrial adenosine diphosphate and intramitochondrial adenosine triphosphate across the inner mitochondrial membrane and appears to be a member of the mitochondrial permeability transition pore whose opening induces apoptosis. Genetically or physiologically restricted ANT function associated with insufficient energy supply and induced apoptosis leads to severe cardiac disturbance. In contrast, to counter myocardial stress, heart tissue developed cell protecting gene programs including ANT1 up-regulation to stabilize energy supply and concurrently suppress apoptotic processes. This review describes characteristics of ANT function and expression in cardiovascular diseases and ANT's role in cardioprotection.