Browsing by Subject "Mitochondrial proteins"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease
    (Springer Nature, 2022-01-28) Barbier-Torres, Lucía; Murray, Ben; Yang, Jin Won; Wang, Jiaohong; Matsuda, Michitaka; Robinson, Aaron; Binek, Aleksandra; Fan, Wei; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Luque-Urbano, Maria; Millet, Oscar; Mavila, Nirmala; Peng, Hui; Ramani, Komal; Gottlieb, Roberta; Sun, Zhaoli; Liangpunsakul, Suthat; Seki, Ekihiro; Van Eyk, Jennifer E.; Mato, Jose M.; Lu, Shelly C.; Medicine, School of Medicine
    MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser114 facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Blocking PIN1-MATα1 interaction increased mitochondrial MATα1 levels and protected against alcohol-induced mitochondrial dysfunction and fat accumulation. Normally, MATα1 interacts with mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and fatty acid β-oxidation. Preserving mitochondrial MATα1 content correlates with higher methylation and expression of mitochondrial proteins. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcohol-associated liver disease.
  • Thumbnail Image
    Item
    Metabolic Regulation by the Mitochondrial Phosphatase PTPMT1 Is Required for Hematopoietic Stem Cell Differentiation
    (Elsevier, 2013) Yu, Wen-Mei; Liu, Xia; Shen, Jinhua; Jovanovic, Olga; Pohl, Elena E.; Gerson, Stanton L.; Finkel, Toren; Broxmeyer, Hal E.; Qu, Cheng-Kui; Microbiology and Immunology, School of Medicine
    The regulation and coordination of mitochondrial metabolism with hematopoietic stem cell (HSC) self-renewal and differentiation is not fully understood. Here we report that depletion of PTPMT1, a PTEN-like mitochondrial phosphatase, in inducible or hematopoietic-cell-specific knockout mice resulted in hematopoietic failure due to changes in the cell cycle and a block in the differentiation of HSCs. Surprisingly, the HSC pool was increased by ∼40-fold in PTPMT1 knockout mice. Reintroduction of wild-type PTPMT1, but not catalytically deficient PTPMT1 or truncated PTPMT1 lacking mitochondrial localization, restored differentiation capabilities of PTPMT1 knockout HSCs. Further analyses demonstrated that PTPMT1 deficiency altered mitochondrial metabolism and that phosphatidylinositol phosphate substrates of PTPMT1 directly enhanced fatty-acid-induced activation of mitochondrial uncoupling protein 2. Intriguingly, depletion of PTPMT1 from myeloid, T lymphoid, or B lymphoid progenitors did not cause any defects in lineage-specific knockout mice. This study establishes a crucial role of PTPMT1 in the metabolic regulation of HSC function.