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      SIRT3 regulates fatty acid oxidation via reversible enzyme deacetylation

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          Abstract

          Sirtuins are NAD +-dependent protein deacetylases and mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 1, 2. Mice lacking both SIRT3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins 3. We report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. Livers from mice lacking SIRT3 show higher levels of fatty acid oxidation intermediate products and triglycerides during fasting associated with decreased levels of fatty acid oxidation when compared to wild-type mice. Mass spectrometry analysis of mitochondrial proteins shows that long-chain acyl CoA dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo, and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty acid oxidation disorders during fasting including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty acid utilization during fasting.

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          Most cited references47

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          A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION

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            Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

            Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
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              Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.

              Acetylation of proteins on lysine residues is a dynamic posttranslational modification that is known to play a key role in regulating transcription and other DNA-dependent nuclear processes. However, the extent of this modification in diverse cellular proteins remains largely unknown, presenting a major bottleneck for lysine-acetylation biology. Here we report the first proteomic survey of this modification, identifying 388 acetylation sites in 195 proteins among proteins derived from HeLa cells and mouse liver mitochondria. In addition to regulators of chromatin-based cellular processes, nonnuclear localized proteins with diverse functions were identified. Most strikingly, acetyllysine was found in more than 20% of mitochondrial proteins, including many longevity regulators and metabolism enzymes. Our study reveals previously unappreciated roles for lysine acetylation in the regulation of diverse cellular pathways outside of the nucleus. The combined data sets offer a rich source for further characterization of the contribution of this modification to cellular physiology and human diseases.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                28 December 2009
                4 March 2010
                4 September 2010
                : 464
                : 7285
                : 121-125
                Affiliations
                [1 ] Gladstone Institute of Virology and Immunology, University of California San Francisco, CA
                [2 ] Department of Medicine, University of California, San Francisco
                [3 ] Department of Pediatrics, The Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA
                [4 ] Joslin Diabetes Center, Harvard Medical School, Boston, MA
                [5 ] Howard Hughes Medical Institute, The Children’s Hospital, Department of Genetics, Harvard Medical School, Boston, MA
                [6 ] Gladstone Institute of Cardiovascular Disease, University of California San Francisco, CA
                [7 ] Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham NC
                [8 ] Cell Signaling Technology, Danvers, MA
                [9 ] Department of Medicine, Physiology, and Biophysics and the Diabetes Unit, Boston University Medical Center, Boston, MA
                Author notes

                Author Contributions MH, TS, EG, EJ, CG, CH, SB, and AS performed in vitro, in vivo and biochemical studies; OI, RS, JB performed metabolomic studies; BS, DL, and YL carried out mass spectrometry studies; MH and EV designed the studies, analyzed the data, and wrote the manuscript; all other authors reviewed and commented on the manuscript.

                Article
                nihpa166711
                10.1038/nature08778
                2841477
                20203611
                8ac37bde-95bb-45e8-b6ac-6d65f4903a8d

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                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: U24 DK059637-01 ||DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: R01 DK067509-04 ||DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: R01 DK019514-29 ||DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: P30 DK026743-26A1 ||DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: P01 HL068758-06A1 ||HL
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: K08 AG022325-01A1 ||AG
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Funded by: National Institute on Aging : NIA
                Funded by: Howard Hughes Medical Institute
                Award ID: ||HHMI_
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