Background: In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria.
Objectives: The authors aimed to determine the role of the calcineurin splicing variant CnAβ1 in the context of cardiac hypertrophy and its mechanism of action.
Methods: Transgenic mice overexpressing CnAβ1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAβ1 (CnAβ1 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses.
Results: In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAβ1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAβ1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAβ1. CnAβ1 mice show increased cardiac hypertrophy and declined contractility.
Conclusions: The metabolic reprogramming induced by CnAβ1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches.
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http://dx.doi.org/10.1016/j.jacc.2017.11.067 | DOI Listing |
Cancer Res
January 2025
Medical Department of Hematology, Oncology and Tumor Immunology, Molekulares Krebsforschungszentrum - MKFZ, Campus Virchow Klinikum, Charité - Universitätsmedizin, Berlin, Germany.
Metabolites
December 2024
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
ALDH1L1 plays a crucial role in folate metabolism, regulating the flow of one-carbon groups through the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO in a NADP-dependent reaction. The downregulation of ALDH1L1 promotes malignant tumor growth, and silencing of ALDH1L1 is commonly observed in many cancers. In a previous study, knockout (KO) mice were found to have an altered liver metabotype, including significant alterations in glycine and serine.
View Article and Find Full Text PDFOne-carbon metabolism (OCM) is a series of connected pathways involving the methionine-folate cycles, transsulfuration, polyamine synthesis, nucleotide synthesis, free-radical scavenging, and energy metabolism. These pathways functionally depend upon amino acids (methionine, glycine, and serine), vitamins (folate, B, B, and B), and minerals (sulfur, cobalt, and zinc). Growing bodies of research indicate that in beef cattle, physiological stage, nutritional plane, diet, species (Bos taurus vs.
View Article and Find Full Text PDFBMC Cancer
December 2024
Joint National Laboratory for Antibody Drug Engineering, School of Medicine, Henan University, Kaifeng, 475004, China.
Background: Serine/glycine are critical for the growth and survival of cancer cells. Some cancer cells are more dependent on exogenous serine/glycine than endogenously synthesized serine/glycine. However, the function and underlying mechanisms of exogenous serine/glycine in renal cell carcinoma (RCC) remain unclear.
View Article and Find Full Text PDFFunct Integr Genomics
December 2024
Department of Infectious Disease, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, No.20 Jinyu Road, Yubei District, Chongqing, 401122, China.
Metastasis is responsible for approximately 90% of lethality from solid tumors. Metabolic abnormalities are one of the key characteristics of tumor cells, closely associated with tumorigenesis and progression. The de novo synthesis pathway of serine is a key metabolic bypass in glycolysis, which could provide material and energy basis for the rapid proliferation of tumor cells by mediating one-carbon metabolism.
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