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  1. Article: Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin.

    Bernardo-Seisdedos, Ganeko / Schedlbauer, Andreas / Pereira-Ortuzar, Tania / Mato, José M / Millet, Oscar

    Life (Basel, Switzerland)

    2023  Volume 13, Issue 1

    Abstract: 1) Background: Human frataxin is an iron binding protein that participates in the biogenesis of iron sulfur clusters and enhances ferrochelatase activity. While frataxin association to other proteins has been extensively characterized up to the ... ...

    Abstract (1) Background: Human frataxin is an iron binding protein that participates in the biogenesis of iron sulfur clusters and enhances ferrochelatase activity. While frataxin association to other proteins has been extensively characterized up to the structural level, much less is known about the putative capacity of frataxin to interact with functionally related metabolites. In turn, current knowledge about frataxin's capacity to coordinate metal ions is limited to iron (II and III); (2) Methods: here, we used NMR spectroscopy, Molecular Dynamics, and Docking approaches to demonstrate new roles of frataxin; (3) Results: We demonstrate that frataxin also binds Zn
    Language English
    Publishing date 2023-01-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662250-6
    ISSN 2075-1729
    ISSN 2075-1729
    DOI 10.3390/life13010222
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  2. Article: Metabolomics as a powerful tool for diagnostic, pronostic and drug intervention analysis in COVID-19.

    Bruzzone, Chiara / Conde, Ricardo / Embade, Nieves / Mato, José M / Millet, Oscar

    Frontiers in molecular biosciences

    2023  Volume 10, Page(s) 1111482

    Abstract: COVID-19 currently represents one of the major health challenges worldwide. Albeit its infectious character, with onset affectation mainly at the respiratory track, it is clear that the pathophysiology of COVID-19 has a systemic character, ultimately ... ...

    Abstract COVID-19 currently represents one of the major health challenges worldwide. Albeit its infectious character, with onset affectation mainly at the respiratory track, it is clear that the pathophysiology of COVID-19 has a systemic character, ultimately affecting many organs. This feature enables the possibility of investigating SARS-CoV-2 infection using multi-omic techniques, including metabolomic studies by chromatography coupled to mass spectrometry or by nuclear magnetic resonance (NMR) spectroscopy. Here we review the extensive literature on metabolomics in COVID-19, that unraveled many aspects of the disease including: a characteristic metabotipic signature associated to COVID-19, discrimination of patients according to severity, effect of drugs and vaccination treatments and the characterization of the natural history of the metabolic evolution associated to the disease, from the infection onset to full recovery or long-term and long sequelae of COVID.
    Language English
    Publishing date 2023-02-15
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2023.1111482
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  3. Article ; Online: Impaired Hepatic Very Low-Density Lipoprotein Secretion Promotes Tumorigenesis and Is Accelerated with Fabp1 Deletion.

    Newberry, Elizabeth P / Molitor, Elizabeth A / Liu, Allen / Chong, Kamyar / Liu, Xiuli / Alonso, Cristina / Mato, Jose M / Davidson, Nicholas O

    The American journal of pathology

    2024  

    Abstract: Genetic polymorphisms that impair very low-density lipoprotein (VLDL) secretion are linked to hepatic steatosis, fibrosis, and hepatocellular cancer. Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, ... ...

    Abstract Genetic polymorphisms that impair very low-density lipoprotein (VLDL) secretion are linked to hepatic steatosis, fibrosis, and hepatocellular cancer. Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO X Fabp1-null [Fabp1/Mttp double knockout (DKO)] mice. Here, we examine the impact of impaired VLDL secretion in Mttp-LKO mice on hepatocellular cancer incidence and progression in comparison to Fabp1/Mttp DKO mice. Diethylnitrosamine-treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared with flox controls, whereas diethylnitrosamine-treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Serum high-density lipoprotein cholesterol was elevated in both Mttp-LKO and Fabp1/Mttp DKO mice, with increased intratumoral expression of apolipoprotein A1 and apolipoprotein E. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNA sequencing revealed mRNA changes suggesting altered monocarboxylic acid use and increased aerobic glycolysis, whereas hepatocytes from Fabp1/Mttp DKO mice exhibited increased capacity to use glucose and glutamine. These metabolic shifts were accompanied by reduced expression of HNF1a, which correlated with tumor burden. Taken together, these findings demonstrate that hepatic tumorigenesis is increased in mice with impaired VLDL secretion and further accelerated via pathways including altered fatty acid compartmentalization and shifts in hepatic energy use.
    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2943-9
    ISSN 1525-2191 ; 0002-9440
    ISSN (online) 1525-2191
    ISSN 0002-9440
    DOI 10.1016/j.ajpath.2024.02.005
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  4. Article: Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review.

    Noureddin, Mazen / Sander-Struckmeier, Suntje / Mato, José M

    World journal of hepatology

    2020  Volume 12, Issue 2, Page(s) 46–63

    Abstract: Background: S-adenosylmethionine (AdoMet) is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis (IHC) and chronic liver diseases. While the efficacy of AdoMet has been demonstrated previously, it has not been systematically ... ...

    Abstract Background: S-adenosylmethionine (AdoMet) is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis (IHC) and chronic liver diseases. While the efficacy of AdoMet has been demonstrated previously, it has not been systematically investigated within the early weeks of treatment.
    Aim: To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.
    Methods: Studies reporting the efficacy of intravenous, intramuscular, or oral forms of AdoMet within 8 wk of treatment initiation were considered; three randomized and six non-randomized studies were eligible for inclusion (PROSPERO registration number CRD42018090936). Of the three randomized studies, two were double-blind and placebo-controlled, and one was comparator-controlled with unclear blinding and a relatively high risk of bias. Mean serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) following AdoMet treatment
    Results: Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet
    Conclusion: Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk, with further improvements observed in some studies after 4 and 8 wk of treatment.
    Language English
    Publishing date 2020-02-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2573703-X
    ISSN 1948-5182
    ISSN 1948-5182
    DOI 10.4254/wjh.v12.i2.46
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  5. Article ; Online: The use of pharmacological chaperones in rare diseases caused by reduced protein stability.

    Gil-Martínez, Jon / Bernardo-Seisdedos, Ganeko / Mato, José M / Millet, Oscar

    Proteomics

    2022  Volume 22, Issue 23-24, Page(s) e2200222

    Abstract: Rare diseases are most often caused by inherited genetic disorders that, after translation, will result in a protein with altered function. Decreased protein stability is the most frequent mechanism associated with a congenital pathogenic missense ... ...

    Abstract Rare diseases are most often caused by inherited genetic disorders that, after translation, will result in a protein with altered function. Decreased protein stability is the most frequent mechanism associated with a congenital pathogenic missense mutation and it implies the destabilization of the folded conformation in favour of unfolded or misfolded states. In the cellular context and when experimental data is available, a mutant protein with altered thermodynamic stability often also results in impaired homeostasis, with the deleterious accumulation of protein aggregates, metabolites and/or metabolic by-products. In the last decades, a significant effort has enabled the characterization of rare diseases associated to protein stability defects and triggered the development of innovative therapeutic intervention lines, say, the use of pharmacological chaperones to correct the intracellular impaired homeostasis. Here, we review the current knowledge on rare diseases caused by reduced protein stability, paying special attention to the thermodynamic aspects of the protein destabilization, also focusing on some examples where pharmacological chaperones are being tested.
    MeSH term(s) Humans ; Protein Folding ; Molecular Chaperones ; Rare Diseases/drug therapy ; Protein Stability ; Protein Aggregates
    Chemical Substances Molecular Chaperones ; Protein Aggregates
    Language English
    Publishing date 2022-10-19
    Publishing country Germany
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2032093-0
    ISSN 1615-9861 ; 1615-9853
    ISSN (online) 1615-9861
    ISSN 1615-9853
    DOI 10.1002/pmic.202200222
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  6. Article ; Online: S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver.

    Barbier-Torres, Lucía / Chhimwal, Jyoti / Kim, So Yeon / Ramani, Komal / Robinson, Aaron / Yang, Heping / Van Eyk, Jenny / Liangpunsakul, Suthat / Seki, Ekihiro / Mato, José M / Lu, Shelly C

    International journal of biological sciences

    2024  Volume 20, Issue 4, Page(s) 1218–1237

    Abstract: MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is ... ...

    Abstract MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced
    MeSH term(s) Humans ; S-Adenosylmethionine/metabolism ; Electron Transport ; Liver/metabolism ; Mitochondria/metabolism ; Liver Diseases, Alcoholic/metabolism
    Chemical Substances S-Adenosylmethionine (7LP2MPO46S)
    Language English
    Publishing date 2024-01-27
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2179208-2
    ISSN 1449-2288 ; 1449-2288
    ISSN (online) 1449-2288
    ISSN 1449-2288
    DOI 10.7150/ijbs.90104
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  7. Article ; Online: Metabolomics as a powerful tool for diagnostic, pronostic and drug intervention analysis in COVID-19

    Chiara Bruzzone / Ricardo Conde / Nieves Embade / José M. Mato / Oscar Millet

    Frontiers in Molecular Biosciences, Vol

    2023  Volume 10

    Abstract: COVID-19 currently represents one of the major health challenges worldwide. Albeit its infectious character, with onset affectation mainly at the respiratory track, it is clear that the pathophysiology of COVID-19 has a systemic character, ultimately ... ...

    Abstract COVID-19 currently represents one of the major health challenges worldwide. Albeit its infectious character, with onset affectation mainly at the respiratory track, it is clear that the pathophysiology of COVID-19 has a systemic character, ultimately affecting many organs. This feature enables the possibility of investigating SARS-CoV-2 infection using multi-omic techniques, including metabolomic studies by chromatography coupled to mass spectrometry or by nuclear magnetic resonance (NMR) spectroscopy. Here we review the extensive literature on metabolomics in COVID-19, that unraveled many aspects of the disease including: a characteristic metabotipic signature associated to COVID-19, discrimination of patients according to severity, effect of drugs and vaccination treatments and the characterization of the natural history of the metabolic evolution associated to the disease, from the infection onset to full recovery or long-term and long sequelae of COVID.
    Keywords COVID-19 ; SARS-CoV-2 infection ; metabolomics ; lipidomics ; NMR ; LC/GC-MS ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
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  8. Article ; Online: Liver receptor homolog 1 and transmethylation fluxes in nonalcoholic steatohepatitis.

    Mato, José M / Lu, Shelly C

    Hepatology (Baltimore, Md.)

    2016  Volume 63, Issue 1, Page(s) 17–19

    MeSH term(s) Animals ; Liver/metabolism ; Male ; Methylation ; Receptors, Cytoplasmic and Nuclear/physiology
    Chemical Substances Receptors, Cytoplasmic and Nuclear
    Language English
    Publishing date 2016-01
    Publishing country United States
    Document type Comment ; Editorial
    ZDB-ID 604603-4
    ISSN 1527-3350 ; 0270-9139
    ISSN (online) 1527-3350
    ISSN 0270-9139
    DOI 10.1002/hep.28146
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  9. Article ; Online: One Carbon Metabolism and

    Fernández-Ramos, David / Lopitz-Otsoa, Fernando / Millet, Oscar / Alonso, Cristina / Lu, Shelly C / Mato, José M

    Livers

    2022  Volume 2, Issue 4, Page(s) 243–257

    Abstract: One carbon metabolism (1CM) can be defined as the transfer of a carbon unit from one metabolite to another and its replenishment by different sources of labile methyl-group nutrients: primarily choline, methionine, betaine, and serine. This flow of ... ...

    Abstract One carbon metabolism (1CM) can be defined as the transfer of a carbon unit from one metabolite to another and its replenishment by different sources of labile methyl-group nutrients: primarily choline, methionine, betaine, and serine. This flow of carbon units allows the biosynthesis of nucleotides, amino acids, formylated methionyl-tRNA, polyamines, glutathione, phospholipids, detoxification reactions, maintenance of the redox status and the concentration of NAD, and methylation reactions including epigenetic modifications. That is, 1CM functions as a nutrient sensor and integrator of cellular metabolism. A critical process in 1CM is the synthesis of
    Language English
    Publishing date 2022-10-04
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2673-4389
    ISSN (online) 2673-4389
    DOI 10.3390/livers2040020
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  10. Article ; Online: Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease.

    Mato, José M / Alonso, Cristina / Noureddin, Mazen / Lu, Shelly C

    World journal of gastroenterology

    2019  Volume 25, Issue 24, Page(s) 3009–3020

    Abstract: Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, ...

    Abstract Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy. NAFLD covers a spectrum that ranges from simple steatosis, nonalcoholic steatohepatitis (NASH) with varying degrees of fibrosis, to cirrhosis, which is a major risk factor for hepatocellular carcinoma. Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity, type 2 diabetes mellitus and dyslipidemia, with a global prevalence of 25%. NAFLD arises when the uptake of fatty acids (FA) and triglycerides (TG) from circulation and de novo lipogenesis saturate the rate of FA β-oxidation and very-low density lipoprotein (VLDL)-TG export. Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH, and therefore, alterations in liver and serum lipidomic signatures are good indicators of the disease's development and progression. This review focuses on the importance of the classification of NAFLD patients into different subtypes, corresponding to the main alteration(s) in the major pathways that regulate FA homeostasis leading, in each case, to the initiation and progression of NASH. This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.
    MeSH term(s) Biomarkers/blood ; Biomarkers/metabolism ; Disease Progression ; Global Burden of Disease ; Humans ; Lipid Metabolism ; Lipids/blood ; Liver/metabolism ; Liver/pathology ; Non-alcoholic Fatty Liver Disease/diagnosis ; Non-alcoholic Fatty Liver Disease/epidemiology ; Non-alcoholic Fatty Liver Disease/metabolism ; Prevalence
    Chemical Substances Biomarkers ; Lipids
    Language English
    Publishing date 2019-07-10
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2185929-2
    ISSN 2219-2840 ; 1007-9327
    ISSN (online) 2219-2840
    ISSN 1007-9327
    DOI 10.3748/wjg.v25.i24.3009
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