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

Tracey A Rouault - One of the best experts on this subject based on the ideXlab platform.

  • human Iron sulfur cluster assembly cellular Iron Homeostasis and disease
    Biochemistry, 2010
    Co-Authors: Tracey A Rouault
    Abstract:

    Iron−sulfur (Fe−S) proteins contain prosthetic groups consisting of two or more Iron atoms bridged by sulfur ligands, which facilitate multiple functions, including redox activity, enzymatic function, and maintenance of structural integrity. More than 20 proteins are involved in the biosynthesis of Iron−sulfur clusters in eukaryotes. Defective Fe−S cluster synthesis not only affects activities of many Iron−sulfur enzymes, such as aconitase and succinate dehydrogenase, but also alters the regulation of cellular Iron Homeostasis, causing both mitochondrial Iron overload and cytosolic Iron deficiency. In this work, we review human Fe−S cluster biogenesis and human diseases that are caused by defective Fe−S cluster biogenesis. Fe−S cluster biogenesis takes place essentially in every tissue of humans, and products of human disease genes, including frataxin, GLRX5, ISCU, and ABCB7, have important roles in the process. However, the human diseases, Friedreich ataxia, glutaredoxin 5-deficient sideroblastic anemia,...

  • functions of mitochondrial iscu and cytosolic iscu in mammalian Iron sulfur cluster biogenesis and Iron Homeostasis
    Cell Metabolism, 2006
    Co-Authors: Winghang Tong, Tracey A Rouault
    Abstract:

    Iron-sulfur (Fe-S) clusters are required for the functions of mitochondrial aconitase, mammalian Iron regulatory protein 1, and many other proteins in multiple subcellular compartments. Recent studies in Saccharomyces cerevisiae indicated that Fe-S cluster biogenesis also has an important role in mitochondrial Iron Homeostasis. Here we report the functional analysis of the mitochondrial and cytosolic isoforms of the human Fe-S cluster scaffold protein, ISCU. Suppression of human ISCU by RNAi not only inactivated mitochondrial and cytosolic aconitases in a compartment-specific manner but also inappropriately activated the Iron regulatory proteins and disrupted intracellular Iron Homeostasis. Furthermore, endogenous ISCU levels were suppressed by Iron deprivation. These results provide evidence for a coordinated response to Iron deficiency that includes activation of Iron uptake, redistribution of intracellular Iron, and decreased utilization of Iron in Fe-S proteins.

  • Iron sulphur cluster biogenesis and mitochondrial Iron Homeostasis
    Nature Reviews Molecular Cell Biology, 2005
    Co-Authors: Tracey A Rouault, Winghang Tong
    Abstract:

    Iron–sulphur clusters are important cofactors for proteins that are involved in many cellular processes, including electron transport, enzymatic catalysis and regulation. The enzymes that catalyse the formation of Iron–sulphur clusters are widely conserved from bacteria to humans. Recent studies in model systems and humans reveal that Iron–sulphur proteins have important roles in mitochondrial Iron Homeostasis and in the pathogenesis of the human disease Friedreich ataxia.

Xiaoyan Yang - One of the best experts on this subject based on the ideXlab platform.

  • sirtuin 2 regulates cellular Iron Homeostasis via deacetylation of transcription factor nrf2
    Journal of Clinical Investigation, 2017
    Co-Authors: Xiaoyan Yang, Hsiang Chun Chang, Konrad T Sawicki, Philip W. Burridge, Jason S Shapiro, Chunlei Chen, Meng Shang, Seong Hoon Park, Athanassios Vassilopoulos, Conrad L Epting
    Abstract:

    Abstract SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require Iron, we hypothesized that SIRT2 directly regulates cellular Iron Homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular Iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular Iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels. The reduction in nuclear NRF2 leads to reduced ferroportin 1 (FPN1) expression, which in turn results in decreased cellular Iron export. Finally, we observed that Sirt2 deletion reduced cell viability in response to Iron deficiency. Moreover, livers from Sirt2-/- mice had decreased Iron levels, while this effect was reversed in Sirt2-/- Nrf2-/- double-KO mice. Taken together, our results uncover a link between sirtuin proteins and direct control over cellular Iron Homeostasis via regulation of NRF2 deacetylation and stability.

  • abstract 92 sirtuin 2 mediated deacetylation regulates cellular Iron Homeostasis
    Circulation Research, 2014
    Co-Authors: Xiaoyan Yang, David Gius, Seong Hoon Park, Athanassios Vassilopoulos, Hossein Ardehali
    Abstract:

    Background: Sirtuins (SIRTs) are NAD+-dependent deacetylases, which regulate energy metabolism and response to oxidative stress in the heart. Iron is essential for these processes but is toxic when present in excess. However, whether SIRTs are involved in maintaining cellular Iron Homeostasis is not known. SIRT2 is among the least characterized SIRTs and is mainly present in the cytoplasm. We hypothesized that SIRT2 is required for cellular Iron Homeostasis. Methods and Results: Iron content was significantly lower in SIRT2-/- mouse embryonic fibroblasts (MEFs) compared to SIRT2+/+ MEFs (non-heme Iron: 0.073 vs. 0.060 nmol/μg protein, p=0.02), andlevels of ferroportin-1 (FPN1), the major cellular Iron exporter, was significantly increased in SIRT2-/- MEFs. Similarly, silencing SIRT2 in HepG2 cells decreased cellular Iron levels and increased FPN1 expression, indicating that enhanced FPN1 with SIRT2 downregulation drove Iron export and caused a reduction in cellular Iron levels. Furthermore, Iron export as...

Roland Lill - One of the best experts on this subject based on the ideXlab platform.

  • human cia2a fam96a and cia2b fam96b integrate Iron Homeostasis and maturation of different subsets of cytosolic nuclear Iron sulfur proteins
    Cell Metabolism, 2013
    Co-Authors: Oliver Stehling, Roland Lill, Ajay A Vashisht, Judita Mascarenhas, Alex D Sheftel, Brigitte Niggemeyer, Ralf Rosser, Antonio J Pierik, James A Wohlschlegel
    Abstract:

    Numerous cytosolic and nuclear proteins involved in metabolism, DNA maintenance, protein translation, or Iron Homeostasis depend on Iron-sulfur (Fe/S) cofactors, yet their assembly is poorly defined. Here, we identify and characterize human CIA2A (FAM96A), CIA2B (FAM96B), and CIA1 (CIAO1) as components of the cytosolic Fe/S protein assembly (CIA) machinery. CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19. The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins. In contrast, CIA2A specifically matures Iron regulatory protein 1 (IRP1), which is critical for cellular Iron Homeostasis. Surprisingly, a second layer of Iron regulation involves the stabilization of IRP2 by CIA2A binding or upon depletion of CIA2B or MMS19, even though IRP2 lacks an Fe/S cluster. In summary, CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly and intimately link this process to cellular Iron regulation via IRP1 Fe/S cluster maturation and IRP2 stabilization.

  • the abc transporter atm1p is required for mitochondrial Iron Homeostasis
    FEBS Letters, 1997
    Co-Authors: Gyula Kispal, Peter Csere, Bernard Guiard, Roland Lill
    Abstract:

    The function of the ABC transporter Atm1p located in the mitochondrial inner membrane is not yet known. To study its cellular role, we analyzed a mutant in which ATM1 was disrupted. Δatm1 cells are deficient in the holoforms, but not the apoforms of heme-carrying proteins both within and outside mitochondria, yet both synthesis and transport of heme are functional. Δatm1 cells are hypersensitive for growth in the presence of oxidative reagents, and they contain increased levels of the antioxidant glutathione, in particular of its oxidized form. Mitochondria deficient in Atm1p accumulate 30-fold higher levels of free Iron as compared to wild-type organelles, i.e. three-fold more than mitochondria deficient in frataxin, the protein mutated in Friedreich's ataxia. The increased mitochondrial Iron content may be causative of the oxidative damage of heme-containing proteins in Δatm1 cells. Our data assign an important function to Atm1p in mitochondrial Iron Homeostasis.

Julian P Whitelegge - One of the best experts on this subject based on the ideXlab platform.

  • regulation of Iron Homeostasis through parkin mediated lactoferrin ubiquitylation
    Biochemistry, 2020
    Co-Authors: Ankur A Gholkar, Stefan Schmollinger, Erick F Velasquez, Whitaker Cohn, Joseph Capri, Harish Dharmarajan, William J Deardorff, Lucy W Gao, Mai Abdusamad, Julian P Whitelegge
    Abstract:

    Somatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of Iron Homeostasis have both been linked to Parkinson’s disease. Lactotransferrin (LTF) is a member of the fam...

  • regulation of Iron Homeostasis through parkin mediated lactoferrin ubiquitylation
    bioRxiv, 2020
    Co-Authors: Ankur A Gholkar, Stefan Schmollinger, Erick F Velasquez, Whitaker Cohn, Joseph Capri, Harish Dharmarajan, William J Deardorff, Lucy W Gao, Mai Abdusamad, Julian P Whitelegge
    Abstract:

    Somatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of Iron Homeostasis have both been linked to Parkinson9s disease. Lactotransferrin is a member of the transferrin Iron binding proteins that regulate Iron Homeostasis and increased levels of Lactotransferrin and its receptor have been observed in neurodegenerative disorders like Parkinson9s disease. Here, we report that Parkin binds to Lactotransferrin and ubiquitylates it to regulate Iron Homeostasis.

Conrad L Epting - One of the best experts on this subject based on the ideXlab platform.

  • sirtuin 2 regulates cellular Iron Homeostasis via deacetylation of transcription factor nrf2
    Journal of Clinical Investigation, 2017
    Co-Authors: Xiaoyan Yang, Hsiang Chun Chang, Konrad T Sawicki, Philip W. Burridge, Jason S Shapiro, Chunlei Chen, Meng Shang, Seong Hoon Park, Athanassios Vassilopoulos, Conrad L Epting
    Abstract:

    Abstract SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require Iron, we hypothesized that SIRT2 directly regulates cellular Iron Homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular Iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular Iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels. The reduction in nuclear NRF2 leads to reduced ferroportin 1 (FPN1) expression, which in turn results in decreased cellular Iron export. Finally, we observed that Sirt2 deletion reduced cell viability in response to Iron deficiency. Moreover, livers from Sirt2-/- mice had decreased Iron levels, while this effect was reversed in Sirt2-/- Nrf2-/- double-KO mice. Taken together, our results uncover a link between sirtuin proteins and direct control over cellular Iron Homeostasis via regulation of NRF2 deacetylation and stability.