The Experts below are selected from a list of 243 Experts worldwide ranked by ideXlab platform
William Valdar - One of the best experts on this subject based on the ideXlab platform.
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candidate risk Factors and mechanisms for tolvaptan induced liver injury are identified using a collaborative cross approach
Toxicological Sciences, 2017Co-Authors: Merrie Mosedale, William J. Brock, Sharin E Roth, Yunjung Kim, Tim Wiltshire, Scott J Eaddy, Gregory R Keele, Robert W Corty, Yuying Xie, William ValdarAbstract:Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk Factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains. Genetic mapping coupled with transcriptomic analysis in the liver was used to identify several candidate susceptibility genes including epoxide hydrolase 2, interferon regulatory Factor 3, and Mitochondrial Fission Factor. Gene pathway analysis revealed that oxidative stress and immune response pathways were activated in response to tolvaptan treatment across all strains, but genes involved in regulation of bile acid homeostasis were most associated with tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase inhibitor (Slpi) mRNA was also induced in the susceptible strains and was associated with increased plasma levels of Slpi protein, suggesting a potential serum marker for DILI susceptibility. In summary, tolvaptan induced signs of oxidative stress, Mitochondrial dysfunction, and innate immune response in all strains, but variation in bile acid homeostasis was most associated with susceptibility to the liver response. This CC study has indicated potential mechanisms underlying tolvaptan DILI and biomarkers of susceptibility that may be useful in managing the risk of DILI in ADPKD patients.
Eun Kyung Lee - One of the best experts on this subject based on the ideXlab platform.
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microRNA-200a-3p enhances Mitochondrial elongation by targeting Mitochondrial Fission Factor.
BMB reports, 2017Co-Authors: Heejin Lee, Hyosun Tak, So Jung Park, Dong-hyung Cho, Eun Kyung LeeAbstract:Mitochondria play pivotal roles in the ATP production, apoptosis and generation of reactive oxygen species. Although dynamic regulation of mitochondria morphology is a critical step to maintain cellular homeostasis, the regulatory mechanisms are not yet fully elucidated. In this study, we identified miR-200a-3p as a novel regulator of Mitochondrial dynamics by targeting Mitochondrial Fission Factor (MFF). We demonstrated that the ectopic expression of miR-200a-3p enhanced Mitochondrial elongation, Mitochondrial ATP synthesis, Mitochondrial membrane potential and oxygen consumption rate. These results indicate that miR-200a-3p positively regulates Mitochondrial elongation by downregulating MFF expression. [BMB Reports 2017; 50(4): 214-219].
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mir 27 regulates Mitochondrial networks by directly targeting the Mitochondrial Fission Factor
Experimental and Molecular Medicine, 2014Co-Authors: Hyosun Tak, Heejin Lee, Dong-hyung Cho, Jihye Kim, Aravinth Kumar Jayabalan, Hoin Kang, Takbum Ohn, Suk Woo Nam, Wook Kim, Eun Kyung LeeAbstract:Mitochondrial morphology is dynamically regulated by forming small, fragmented units or interconnected networks, and this is a pivotal process that is used to maintain Mitochondrial homeostasis. Although dysregulation of Mitochondrial dynamics is related to the pathogenesis of several human diseases, its molecular mechanism is not fully elucidated. In this study, we demonstrate the potential role of miR-27 in the regulation of Mitochondrial dynamics. Mitochondrial Fission Factor (MFF) mRNA is a direct target of miR-27, whose ectopic expression decreases MFF expression through binding to its 3′-untranslated region. Expression of miR-27 results in the elongation of mitochondria as well as an increased Mitochondrial membrane potential and Mitochondrial ATP level. Our results suggest that miR-27 is a novel regulator affecting morphological Mitochondrial changes by targeting MFF.
Ueli Suter - One of the best experts on this subject based on the ideXlab platform.
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GDAP1 mutations differ in their effects on Mitochondrial dynamics and apoptosis depending on the mode of inheritance
Neurobiology of disease, 2009Co-Authors: Axel Niemann, Konstanze Marion Wagner, Marcel Ruegg, Ueli SuterAbstract:Mutations in the GDAP1 gene lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease; CMT). Here, we demonstrate that GDAP1 is a Mitochondrial Fission Factor whose activity is dependent on the Fission Factors Drp1 and Fis1. Unlike other Mitochondrial Fission Factors, GDAP1 overexpression or knockdown does not influence the susceptibility of cells to apoptotic stimuli. Recessively inherited CMT-associated forms of GDAP1 (rmGDAP1s) have reduced Fission activity, whereas dominantly inherited forms (dmGDAP1s) interfere with Mitochondrial fusion. Only the expression of dmGDAP1s increases the production of ROS, leads to uneven Mitochondrial transmembrane potentials, and enhances the susceptibility to apoptotic stimuli. Taken together, our results indicate that wild-type GDAP1 promotes Fission without increasing the risk of apoptosis. In CMT, recessive GDAP1 mutations are associated with reduced Fission activity, while dominant mutations impair Mitochondrial fusion and cause Mitochondrial damage. Thus, different cellular mechanisms that disturb Mitochondrial dynamics underlie the similar clinical manifestations caused by GDAP1 mutations, depending on the mode of inheritance.
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Targeting and function of the Mitochondrial Fission Factor GDAP1 are dependent on its tail-anchor.
PloS one, 2009Co-Authors: Konstanze Marion Wagner, Axel Niemann, Marcel Ruegg, Ueli SuterAbstract:Proteins controlling Mitochondrial dynamics are often targeted to and anchored into the Mitochondrial outer membrane (MOM) by their carboxyl-terminal tail-anchor domain (TA). However, it is not known whether the TA modulates protein function. GDAP1 is a Mitochondrial Fission Factor with two neighboring hydrophobic domains each flanked by basic amino acids (aa). Here we define GDAP1 as TA MOM protein. GDAP1 carries a single transmembrane domain (TMD) that is, together with the adjacent basic aa, critical for MOM targeting. The flanking N-terminal region containing the other hydrophobic domain is located in the cytoplasm. TMD sequence, length, and high hydrophobicity do not influence GDAP1 Fission function if MOM targeting is maintained. The basic aa bordering the TMD in the cytoplasm, however, are required for both targeting of GDAP1 as part of the TA and GDAP1-mediated Fission. Thus, this GDAP1 region contains critical overlapping motifs defining intracellular targeting by the TA concomitant with functional aspects.
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schwann cells and the pathogenesis of inherited motor and sensory neuropathies charcot marie tooth disease
Glia, 2006Co-Authors: Philipp Berger, Axel Niemann, Ueli SuterAbstract:Over the last 15 years, a number of mutations in a variety of genes have been identified that lead to inherited motor and sensory neuropathies (HMSN), also called Charcot-MarieTooth disease (CMT). In this review we will focus on the molecular and cellular mechanisms that cause the Schwann cell pathologies observed in dysmyelinating and demyelinating forms of CMT. In most instances, the underlying gene defects alter primarily myelinating Schwann cells followed by secondary axonal degeneration. The first set of proteins affected by disease-causing mutations includes the myelin components PMP22, P0/MPZ, Cx32/GJB1, and periaxin. A second group contains the regulators of myelin gene transcription EGR2/Krox20 and SOX10. A third group is composed of intracellular Schwann cells proteins that are likely to be involved in the synthesis, transport and degradation of myelin components. These include the myotubularin-related lipid phosphatase MTMR2 and its regulatory binding partner MTMR13/SBF2, SIMPLE, and potentially also dynamin 2. Mutations affecting the Mitochondrial Fission Factor GDAP1 may indicate an important contribution of mitochondria in myelination or myelin maintenance, whereas the functions of other identified genes, including NDRG1, KIAA1985, and the tyrosyl-tRNA synthase YARS, are not yet clear. Mutations in GDAP1, YARS, and the pleckstrin homology domain of dynamin 2 lead to an intermediate form of CMT that is characterized by moderately reduced nerve conduction velocity consistent with minor myelin deficits. Whether these phenotypes originate in Schwann cells or in neurons, or whether both cell types are directly affected, remains a challenging question. However, based on the advances in systematic gene identification in CMT and the analyses of the function and dysfunction of the affected proteins, crucially interconnected pathways in Schwann cells in health and disease have started to emerge. These networks include the control of myelin formation and stability, membrane trafficking, intracellular protein sorting and quality control, and may extend to Mitochondrial dynamics and basic protein biosynthesis. V C 2006 Wiley-Liss, Inc.
Hyosun Tak - One of the best experts on this subject based on the ideXlab platform.
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microRNA-200a-3p enhances Mitochondrial elongation by targeting Mitochondrial Fission Factor.
BMB reports, 2017Co-Authors: Heejin Lee, Hyosun Tak, So Jung Park, Dong-hyung Cho, Eun Kyung LeeAbstract:Mitochondria play pivotal roles in the ATP production, apoptosis and generation of reactive oxygen species. Although dynamic regulation of mitochondria morphology is a critical step to maintain cellular homeostasis, the regulatory mechanisms are not yet fully elucidated. In this study, we identified miR-200a-3p as a novel regulator of Mitochondrial dynamics by targeting Mitochondrial Fission Factor (MFF). We demonstrated that the ectopic expression of miR-200a-3p enhanced Mitochondrial elongation, Mitochondrial ATP synthesis, Mitochondrial membrane potential and oxygen consumption rate. These results indicate that miR-200a-3p positively regulates Mitochondrial elongation by downregulating MFF expression. [BMB Reports 2017; 50(4): 214-219].
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T-cell-restricted intracellular antigen 1 facilitates Mitochondrial fragmentation by enhancing the expression of Mitochondrial Fission Factor
Cell Death & Differentiation, 2017Co-Authors: Hyosun Tak, Heejin Lee, So Jung Park, Dong-hyung Cho, Jihye Kim, Hoin Kang, Jung Woo Eun, Chongtae Kim, Kyungbun Lee, Wook KimAbstract:Mitochondrial morphology is dynamically regulated by the formation of small fragmented units or interconnected Mitochondrial networks, and this dynamic morphological change is a pivotal process in normal Mitochondrial function. In the present study, we identified a novel regulator responsible for the regulation of Mitochondrial dynamics. An assay using CHANG liver cells stably expressing Mitochondrial-targeted yellow fluorescent protein (mtYFP) and a group of siRNAs revealed that T-cell intracellular antigen protein-1 (TIA-1) affects Mitochondrial morphology by enhancing Mitochondrial Fission. The function of TIA-1 in Mitochondrial dynamics was investigated through various biological approaches and expression analysis in human specimen. Downregulation of TIA-1-enhanced Mitochondrial elongation, whereas ectopic expression of TIA-1 resulted in mitochondria fragmentation. In addition, TIA-1 increased Mitochondrial activity, including the rate of ATP synthesis and oxygen consumption. Further, we identified Mitochondrial Fission Factor (MFF) as a direct target of TIA-1, and showed that TIA-1 promotes Mitochondrial fragmentation by enhancing MFF translation. TIA-1 null cells had a decreased level of MFF and less Mitochondrial Drp1, a critical Factor for Mitochondrial fragmentation, thereby enhancing Mitochondrial elongation. Taken together, our results indicate that TIA-1 is a novel Factor that facilitates Mitochondrial dynamics by enhancing MFF expression and contributes to Mitochondrial dysfunction.
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mir 27 regulates Mitochondrial networks by directly targeting the Mitochondrial Fission Factor
Experimental and Molecular Medicine, 2014Co-Authors: Hyosun Tak, Heejin Lee, Dong-hyung Cho, Jihye Kim, Aravinth Kumar Jayabalan, Hoin Kang, Takbum Ohn, Suk Woo Nam, Wook Kim, Eun Kyung LeeAbstract:Mitochondrial morphology is dynamically regulated by forming small, fragmented units or interconnected networks, and this is a pivotal process that is used to maintain Mitochondrial homeostasis. Although dysregulation of Mitochondrial dynamics is related to the pathogenesis of several human diseases, its molecular mechanism is not fully elucidated. In this study, we demonstrate the potential role of miR-27 in the regulation of Mitochondrial dynamics. Mitochondrial Fission Factor (MFF) mRNA is a direct target of miR-27, whose ectopic expression decreases MFF expression through binding to its 3′-untranslated region. Expression of miR-27 results in the elongation of mitochondria as well as an increased Mitochondrial membrane potential and Mitochondrial ATP level. Our results suggest that miR-27 is a novel regulator affecting morphological Mitochondrial changes by targeting MFF.
Merrie Mosedale - One of the best experts on this subject based on the ideXlab platform.
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candidate risk Factors and mechanisms for tolvaptan induced liver injury are identified using a collaborative cross approach
Toxicological Sciences, 2017Co-Authors: Merrie Mosedale, William J. Brock, Sharin E Roth, Yunjung Kim, Tim Wiltshire, Scott J Eaddy, Gregory R Keele, Robert W Corty, Yuying Xie, William ValdarAbstract:Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk Factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains. Genetic mapping coupled with transcriptomic analysis in the liver was used to identify several candidate susceptibility genes including epoxide hydrolase 2, interferon regulatory Factor 3, and Mitochondrial Fission Factor. Gene pathway analysis revealed that oxidative stress and immune response pathways were activated in response to tolvaptan treatment across all strains, but genes involved in regulation of bile acid homeostasis were most associated with tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase inhibitor (Slpi) mRNA was also induced in the susceptible strains and was associated with increased plasma levels of Slpi protein, suggesting a potential serum marker for DILI susceptibility. In summary, tolvaptan induced signs of oxidative stress, Mitochondrial dysfunction, and innate immune response in all strains, but variation in bile acid homeostasis was most associated with susceptibility to the liver response. This CC study has indicated potential mechanisms underlying tolvaptan DILI and biomarkers of susceptibility that may be useful in managing the risk of DILI in ADPKD patients.