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      Hyperacetylation of Cardiac Mitochondrial Proteins Is Associated with Metabolic Impairment and Sirtuin Downregulation after Chronic Total Body Irradiation of ApoE -/- Mice

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          Abstract

          Chronic exposure to low-dose ionizing radiation is associated with an increased risk of cardiovascular disease. Alteration in energy metabolism has been suggested to contribute to radiation-induced heart pathology, mitochondrial dysfunction being a hallmark of this disease. The goal of this study was to investigate the regulatory role of acetylation in heart mitochondria in the long-term response to chronic radiation. ApoE-deficient C57Bl/6J mice were exposed to low-dose-rate (20 mGy/day) gamma radiation for 300 days, resulting in a cumulative total body dose of 6.0 Gy. Heart mitochondria were isolated and analyzed using quantitative proteomics. Radiation-induced proteome and acetylome alterations were further validated using immunoblotting, enzyme activity assays, and ELISA. In total, 71 proteins showed peptides with a changed acetylation status following irradiation. The great majority (94%) of the hyperacetylated proteins were involved in the TCA cycle, fatty acid oxidation, oxidative stress response and sirtuin pathway. The elevated acetylation patterns coincided with reduced activity of mitochondrial sirtuins, increased the level of Acetyl-CoA, and were accompanied by inactivation of major cardiac metabolic regulators PGC-1 alpha and PPAR alpha. These observations suggest that the changes in mitochondrial acetylation after irradiation is associated with impairment of heart metabolism. We propose a novel mechanism involved in the development of late cardiac damage following chronic irradiation.

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          Most cited references47

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          SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}.

          In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha. In addition, SIRT1 and PGC-1alpha directly interact and can be co-immunoprecipitated as a molecular complex. A single amino acid mutation in the putative ADP-ribosyltransferase domain of SIRT1 inhibits the interaction of SIRT1 with PGC-1alpha but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1alpha is acetylated in vivo. This acetylation is augmented by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. Finally we demonstrate that SIRT1 catalyzes PGC-1alpha deacetylation both in vitro and in vivo. These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1alpha, a coactivator that regulates cellular metabolism.
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            The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.

            Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARalpha in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPARalpha-mediated transcriptional activation of reporter plasmids containing PPARalpha target elements. PGC-1 also enhanced the transactivation activity of a PPARalpha-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARalpha and PGC-1 cooperatively induced the expression of PPARalpha target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase "pulldown" studies revealed that in contrast to the previously reported ligand-independent interaction with PPARgamma, PGC-1 binds PPARalpha in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1-PPARalpha interaction involves an LXXLL domain in PGC-1 and the PPARalpha AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH(2)-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARalpha interacting domains. These results identify PGC-1 as a coactivator of PPARalpha in the transcriptional control of mitochondrial FAO capacity, define separable PPARalpha interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARalpha-PGC-1 interaction are distinct from that of PPARgamma-PGC-1.
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              Acetyl-CoA and the Regulation of Metabolism: Mechanisms and Consequences

              Acetyl-CoA represents a key node in metabolism due to its intersection with many metabolic pathways and transformations. Emerging evidence reveals that cells monitor the levels of acetyl-CoA as a key indicator of their metabolic state, through distinctive protein acetylation modifications dependent on this metabolite. We offer the following conceptual model for understanding the role of this sentinel metabolite in metabolic regulation. High nucleocytosolic acetyl-CoA amounts are a signature of a “growth” or “fed” state and promote its utilization for lipid synthesis and histone acetylation. In contrast, under “survival” or “fasted” states, acetyl-CoA is preferentially directed into the mitochondria to promote mitochondrial-dependent activities such as the synthesis of ATP and ketone bodies. Fluctuations in acetyl-CoA within these subcellular compartments enable the substrate-level regulation of acetylation modifications, but also necessitates the function of sirtuin deacetylases to catalyze removal of spontaneous modifications that might be unintended. Thus, understanding the sources, fates, and consequences of acetyl-CoA as a carrier of two-carbon units has started to reveal its underappreciated but profound influence on the regulation of numerous life processes.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                22 October 2019
                October 2019
                : 20
                : 20
                : 5239
                Affiliations
                [1 ]Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Institute of Radiation Biology, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Zarko.Barjaktarovic@ 123456helmholtz-muenchen.de (Z.B.); atkinson@ 123456helmholtz-muenchen.de (M.J.A.); soile.tapio@ 123456helmholtz-muenchen.de (S.T.)
                [2 ]Agency for Medicines and Medical Devices of Montenegro, 81000 Podgorica, Montenegro
                [3 ]Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 80939 München, Germany; juliane.merl@ 123456helmholtz-muenchen.de (J.M.-P.); hauck@ 123456helmholtz-muenchen.de (S.M.H.)
                [4 ]Institute for Environmental Sciences (IES), Rokkasho, Aomori 039-3213, Japan; tanakaib@ 123456ies.or.jp (I.B.-T.); tanakas@ 123456ies.or.jp (S.T.)
                [5 ]Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), 76 00196 Rome, Italy; anna.saran@ 123456enea.it (A.S.); mariateresa.mancuso@ 123456enea.it (M.M.)
                [6 ]Chair of Radiation Biology, Technical University Munich, 80333 Munich, Germany
                Author notes
                Article
                ijms-20-05239
                10.3390/ijms20205239
                6829468
                31652604
                0408a1c5-33ef-465d-9e73-67f478b66525
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 October 2019
                : 19 October 2019
                Categories
                Article

                Molecular biology
                ionising radiation,chronic exposure,tbi,acetylome,proteomics,sirtuins,heart,mitochondria,cardiovascular disease,ppar alpha

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