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Ophry Pines – One of the best experts on this subject based on the ideXlab platform.

  • yeast Aconitase mitochondrial import is modulated by interactions of its c and n terminal domains and ssa1 2 hsp70
    Scientific Reports, 2018
    Co-Authors: Reut Benmenachem, Katherine Wang, Orly Marcu, Teck Kwang Lim, Qingsong Lin, Ora Schuelerfurman, Ophry Pines

    Abstract:

    Molecules of single proteins, echoforms, can be distributed between two (or more) subcellular locations, a phenomenon which we refer to as dual targeting or dual localization. The yeast Aconitase gene ACO1 (778 amino acids), encodes a single translation product that is nonetheless dual localized to the cytosol and mitochondria by a reverse translocation mechanism. The solved crystal structure of Aconitase isolated from porcine heart mitochondria shows that it has four domains. The first three tightly associated N-terminal domains are tethered to the larger C-terminal fourth domain (C-terminal amino acids 517-778). We have previously shown that the Aconitase C terminal domain constitutes an independent dual targeting signal when fused to mitochondria-targeted passenger-proteins. We show that the Aconitase N and C-terminal domains interact and that this interaction is important for efficient Aconitase post translational import into mitochondria and for Aconitase dual targeting (relative levels of Aconitase echoforms). Our results suggest a “chaperone-like function” of the C terminal domain towards the N terminal domains which can be modulated by Ssa1/2 (cytosolic Hsp70).

  • Yeast Aconitase mitochondrial import is modulated by interactions of its C and N terminal domains and Ssa1/2 (Hsp70)
    Nature Publishing Group, 2018
    Co-Authors: Reut Ben-menachem, Katherine Wang, Orly Marcu, Teck Kwang Lim, Qingsong Lin, Ora Schueler- Furman, Ophry Pines

    Abstract:

    Abstract Molecules of single proteins, echoforms, can be distributed between two (or more) subcellular locations, a phenomenon which we refer to as dual targeting or dual localization. The yeast Aconitase gene ACO1 (778 amino acids), encodes a single translation product that is nonetheless dual localized to the cytosol and mitochondria by a reverse translocation mechanism. The solved crystal structure of Aconitase isolated from porcine heart mitochondria shows that it has four domains. The first three tightly associated N-terminal domains are tethered to the larger C-terminal fourth domain (C-terminal amino acids 517–778). We have previously shown that the Aconitase C terminal domain constitutes an independent dual targeting signal when fused to mitochondria-targeted passenger-proteins. We show that the Aconitase N and C-terminal domains interact and that this interaction is important for efficient Aconitase post translational import into mitochondria and for Aconitase dual targeting (relative levels of Aconitase echoforms). Our results suggest a “chaperone-like function” of the C terminal domain towards the N terminal domains which can be modulated by Ssa1/2 (cytosolic Hsp70)

  • The Aconitase C-terminal domain is an independent dual targeting element.
    Journal of molecular biology, 2011
    Co-Authors: Reut Ben-menachem, Neta Regev-rudzki, Ophry Pines

    Abstract:

    The tricarboxylic acid cycle enzyme Aconitase in yeast is a single translation product, which is dual targeted and distributed between the mitochondria and the cytosol by a unique mechanism involving reverse translocation. There is limited understanding regarding the precise mechanism of reverse translocation across the mitochondrial membranes. Here, we examined the contribution of the mature part of Aconitase to its dual targeting. We created a set of Aconitase mutants harboring two kinds of alterations: (1) point mutations or very small deletions in conserved sites and (2) systematic large deletions. These mutants were screened for their localization by a α-complementation assay, which revealed that the Aconitase fourth domain that is at the C-terminus (amino acids 517–778) is required for Aconitase distribution. Moreover, fusion of this C-terminal domain to mitochondria-targeted passenger proteins such as dihydrofolate reductase and orotidine-5′-phosphate decarboxylase, conferred dual localization on them. These results indicate that the Aconitase C-terminal domain is both necessary and sufficient for dual targeting, thereby functioning as an “independent signal”. In addition, the same C-terminal domain was shown to be necessary for Aconitase efficient posttranslational import into mitochondria.

Leslie C Costello – One of the best experts on this subject based on the ideXlab platform.

  • Mitochondrial Aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues
    Molecular cancer, 2006
    Co-Authors: Keshav K. Singh, Renty B Franklin, Mohamed M. Desouki, Leslie C Costello

    Abstract:

    Background
    In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-Aconitase activity in prostate epithelial cells could be the result of a decreased level of m-Aconitase enzyme and/or the inhibition of existing m-Aconitase. Earlier studies identified zinc as an inhibitor of m-Aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-Aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-Aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines.

  • Mitochondrial Aconitase gene expression is regulated by testosterone and prolactin in prostate epithelial cells .
    The Prostate, 2000
    Co-Authors: Leslie C Costello, Yiyan Liu, Jing Zou, Renty B Franklin

    Abstract:

    BACKGROUND

    m-Aconitase catalyzes the first step leading to the oxidation of citrate via the Krebs cycle. It is a constituitive enzyme in virtually all mammalian cells, found in excess, and is considered to be a regulatory or regulated enzyme. In contrast to these general relationships, prostate secretory epithelial cells possess a uniquely limiting mitochondrial (m-) Aconitase which minimizes the oxidation of citrate. This permits the unique prostate function of accumulating and secreting extraordinarily high levels of citrate. Previous animal studies demonstrated that testosterone and prolactin regulate the level of m-Aconitase specifically in citrate-producing prostate cells. The present studies were conducted to determine if testosterone and prolactin regulated the expression of the m-Aconitase gene in prostate cells, and to determine the effect of the hormones on human prostate cells.

    METHODS

    The studies were conducted with freshly prepared rat ventral, rat lateral, and pig prostate epithelial cells, and with the human malignant cell lines LNCaP and PC-3. The effects of 1 nM testosterone and 3 nM prolactin on the level of m-Aconitase mRNA and on the transcription rate of m-Aconitase were determined.

    RESULTS

    The studies revealed that both prolactin and testosterone increase the levels of m-Aconitase mRNA and the transcription rates of m-Aconitase in rat ventral prostate cells, pig prostate cells, and human malignant prostate cells (LNCaP and PC-3). In contrast, both hormones decreased the level of m-Aconitase mRNA and repressed m-Aconitase gene transcription in rat lateral prostate cells. The hormonal regulation of m-Aconitase corresponded with the levels of m-Aconitase enzyme, m-Aconitase activity, and citrate oxidation.

    CONCLUSIONS

    In addition to the constitutive expression of m-Aconitase, the m-Aconitase gene is testosterone- and prolactin-regulated in specifically targeted prostate cells. The hormonal regulation of m-Aconitase gene expression and biosynthesis of m-Aconitase provide a regulatory mechanism for the oxidation of citrate, and consequently, the level of net citrate production by prostate. The hormonally increased expression and biosynthesis of m-Aconitase in human malignant cells might be involved in the increased citrate oxidation associated with the development of true malignant cells in prostate cancer. Prostate 42:196–202, 2000. © 2000 Wiley-Liss, Inc.

  • zinc causes a shift toward citrate at equilibrium of the m Aconitase reaction of prostate mitochondria
    Journal of Inorganic Biochemistry, 2000
    Co-Authors: Leslie C Costello, Renty B Franklin, Claire M Kennedy

    Abstract:

    Abstract Prostate secretory epithelial cells have the unique function and capability of accumulating and secreting extraordinarily high levels of citrate. To achieve this, these cells possess a uniquely limiting mitochondrial (m)-Aconitase activity that minimizes the oxidation of citrate via the Krebs cycle. The steady-state citrate/isocitrate ratio of mammalian tissues is generally maintained at about 10–11/1, independent of the concentration of citrate, which is the result of the chemical equilibrium reached in the presence of m-Aconitase. In contrast, the citrate/isocitrate ratio of prostate tissue is about 30–40/1. Zinc, which is also accumulated in prostate cells at much higher levels than in other cells, inhibits m-Aconitase activity thereby minimizing citrate oxidation. This current report is concerned with an effect of zinc on the equilibrium of the reaction catalyzed by m-Aconitase. Studies were conducted with mitochondrial extract preparations from rat ventral prostate epithelial cells. With citrate as the initial substrate, the addition of zinc (7–10 μM) to the prostate mitochondrial preparation resulted in a change in the citrate/isocitrate ratio at equilibrium from an average of 10.5/1 to 13.5/1. In contrast, the identical treatment of kidney mitochondrial preparations resulted in no zinc-induced change in the citrate/isocitrate ratio. When either cis -aconitate or isocitrate was employed as the initial substrate, the addition of zinc did not alter the citrate/isocitrate ratio of prostate or kidney preparations. Partial purification of the prostate preparation revealed that the prostate mitochondrial extract contained a putative protein (which we have designated as ‘citrate factor protein’) that is required for the zinc-induced increase in the citrate/isocitrate ratio. This novel effect of zinc provides another mechanism by which it is assured that the accumulation of citrate is maximized in citrate-producing prostate epithelial cells.

Nicole Hansmeier – One of the best experts on this subject based on the ideXlab platform.

  • Impact of ROS-Induced Damage of TCA Cycle Enzymes on Metabolism and Virulence of Salmonella enterica serovar Typhimurium
    Frontiers Media S.A., 2019
    Co-Authors: Janina Noster, Nicole Hansmeier, Marcus Persicke, Tzu-chiao Chao, Lena Krone, Bianca Heppner, Michael Hensel

    Abstract:

    Salmonella enterica serovar Typhimurium (STM) is exposed to reactive oxygen species (ROS) originating from aerobic respiration, antibiotic treatment, and the oxidative burst occurring inside the Salmonella-containing vacuole (SCV) within host cells. ROS damage cellular compounds, thereby impairing bacterial viability and inducing cell death. Proteins containing iron–sulfur (Fe–S) clusters are particularly sensitive and become non-functional upon oxidation. Comprising five enzymes with Fe–S clusters, the TCA cycle is a pathway most sensitive toward ROS. To test the impact of ROS-mediated metabolic perturbations on bacterial physiology, we analyzed the proteomic and metabolic profile of STM deficient in both cytosolic superoxide dismutases (ΔsodAB). Incapable of detoxifying superoxide anions (SOA), endogenously generated SOA accumulate during growth. ΔsodAB showed reduced abundance of Aconitases, leading to a metabolic profile similar to that of an Aconitase-deficient strain (ΔacnAB). Furthermore, we determined a decreased expression of acnA in STM ΔsodAB. While intracellular proliferation in RAW264.7 macrophages and survival of methyl viologen treatment were not reduced for STM ΔacnAB, proteomic profiling revealed enhanced stress response. We conclude that ROS-mediated reduced expression and damage of Aconitase does not impair bacterial viability or virulence, but might increase ROS amounts in STM, which reinforces the bactericidal effects of antibiotic treatment and immune responses of the host

  • Image_5_Impact of ROS-Induced Damage of TCA Cycle Enzymes on Metabolism and Virulence of Salmonella enterica serovar Typhimurium.TIF
    , 2019
    Co-Authors: Janina Noster, Marcus Persicke, Tzu-chiao Chao, Lena Krone, Bianca Heppner, Michael Hensel, Nicole Hansmeier

    Abstract:

    Salmonella enterica serovar Typhimurium (STM) is exposed to reactive oxygen species (ROS) originating from aerobic respiration, antibiotic treatment, and the oxidative burst occurring inside the Salmonella-containing vacuole (SCV) within host cells. ROS damage cellular compounds, thereby impairing bacterial viability and inducing cell death. Proteins containing iron–sulfur (Fe–S) clusters are particularly sensitive and become non-functional upon oxidation. Comprising five enzymes with Fe–S clusters, the TCA cycle is a pathway most sensitive toward ROS. To test the impact of ROS-mediated metabolic perturbations on bacterial physiology, we analyzed the proteomic and metabolic profile of STM deficient in both cytosolic superoxide dismutases (ΔsodAB). Incapable of detoxifying superoxide anions (SOA), endogenously generated SOA accumulate during growth. ΔsodAB showed reduced abundance of Aconitases, leading to a metabolic profile similar to that of an Aconitase-deficient strain (ΔacnAB). Furthermore, we determined a decreased expression of acnA in STM ΔsodAB. While intracellular proliferation in RAW264.7 macrophages and survival of methyl viologen treatment were not reduced for STM ΔacnAB, proteomic profiling revealed enhanced stress response. We conclude that ROS-mediated reduced expression and damage of Aconitase does not impair bacterial viability or virulence, but might increase ROS amounts in STM, which reinforces the bactericidal effects of antibiotic treatment and immune responses of the host.

  • Table_3_Impact of ROS-Induced Damage of TCA Cycle Enzymes on Metabolism and Virulence of Salmonella enterica serovar Typhimurium.XLSX
    , 2019
    Co-Authors: Janina Noster, Marcus Persicke, Tzu-chiao Chao, Lena Krone, Bianca Heppner, Michael Hensel, Nicole Hansmeier

    Abstract:

    Salmonella enterica serovar Typhimurium (STM) is exposed to reactive oxygen species (ROS) originating from aerobic respiration, antibiotic treatment, and the oxidative burst occurring inside the Salmonella-containing vacuole (SCV) within host cells. ROS damage cellular compounds, thereby impairing bacterial viability and inducing cell death. Proteins containing iron–sulfur (Fe–S) clusters are particularly sensitive and become non-functional upon oxidation. Comprising five enzymes with Fe–S clusters, the TCA cycle is a pathway most sensitive toward ROS. To test the impact of ROS-mediated metabolic perturbations on bacterial physiology, we analyzed the proteomic and metabolic profile of STM deficient in both cytosolic superoxide dismutases (ΔsodAB). Incapable of detoxifying superoxide anions (SOA), endogenously generated SOA accumulate during growth. ΔsodAB showed reduced abundance of Aconitases, leading to a metabolic profile similar to that of an Aconitase-deficient strain (ΔacnAB). Furthermore, we determined a decreased expression of acnA in STM ΔsodAB. While intracellular proliferation in RAW264.7 macrophages and survival of methyl viologen treatment were not reduced for STM ΔacnAB, proteomic profiling revealed enhanced stress response. We conclude that ROS-mediated reduced expression and damage of Aconitase does not impair bacterial viability or virulence, but might increase ROS amounts in STM, which reinforces the bactericidal effects of antibiotic treatment and immune responses of the host.