{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T10:46:53Z","timestamp":1782211613028,"version":"3.54.5"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK113172"],"award-info":[{"award-number":["R01 DK113172"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Cardiomyopathy and arrhythmias can be severe presentations in patients with inherited defects of mitochondrial long-chain fatty acid \u03b2-oxidation (FAO). The pathophysiological mechanisms that underlie these cardiac abnormalities remain largely unknown. We investigated the molecular adaptations to a FAO deficiency in the heart using the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We observed enrichment of amino acid metabolic pathways and of ATF4 target genes among the upregulated genes in the LCAD KO heart transcriptome. We also found a prominent activation of the eIF2\u03b1\/ATF4 axis at the protein level that was independent of the feeding status, in addition to a reduction of cardiac protein synthesis during a short period of food withdrawal. These findings are consistent with an activation of the integrated stress response (ISR) in the LCAD KO mouse heart. Notably, charging of several transfer RNAs (tRNAs), such as tRNAGln was decreased in LCAD KO hearts, reflecting a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the ISR in the hearts of mice with muscle-specific deletion of carnitine palmitoyltransferase 2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signalling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.<\/jats:p>\n                    <jats:p>Translational Perspective: The heart relies mainly on mitochondrial fatty acid \u03b2-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signalling pathways such as the integrated stress response.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvac050","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T06:28:02Z","timestamp":1649312882000},"page":"3198-3210","source":"Crossref","is-referenced-by-count":19,"title":["A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6478-3815","authenticated-orcid":false,"given":"Pablo","family":"Ranea-Robles","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, Box 1498, New York, NY 10029 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5120-4404","authenticated-orcid":false,"given":"Natalya N","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Bender","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, Box 1498, New York, NY 10029 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7596-2421","authenticated-orcid":false,"given":"Andrea S","family":"Pereyra","sequence":"additional","affiliation":[{"name":"Brody School of Medicine at East Carolina University, Department of Physiology, and East Carolina Diabetes and Obesity Institute , Greenville, NC 27858 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3803-8461","authenticated-orcid":false,"given":"Jessica M","family":"Ellis","sequence":"additional","affiliation":[{"name":"Brody School of Medicine at East Carolina University, Department of Physiology, and East Carolina Diabetes and Obesity Institute , Greenville, NC 27858 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2812-717X","authenticated-orcid":false,"given":"Brandon","family":"Stauffer","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, Box 1498, New York, NY 10029 , USA"},{"name":"Mount Sinai Genomics, Inc , Stamford, CT 06902 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, Box 1498, New York, NY 10029 , USA"},{"name":"Mount Sinai Genomics, Inc , Stamford, CT 06902 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig B","family":"Thompson","sequence":"additional","affiliation":[{"name":"Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1110-8012","authenticated-orcid":false,"given":"Carmen","family":"Argmann","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, Box 1498, New York, NY 10029 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Puchowicz","sequence":"additional","affiliation":[{"name":"Department of Nutrition, School of Medicine, Case Western Reserve University , Cleveland, OH 44106 , USA"},{"name":"Department of Pediatrics, University of Tennessee Health Science Center , Memphis, TN 38163 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6167-9147","authenticated-orcid":false,"given":"Sander M","family":"Houten","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , 1425 Madison Avenue, Box 1498, New York, NY 10029 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"2022122915250242200_cvac050-B1","first-page":"H742","article-title":"Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts","volume":"267","author":"Allard","year":"1994","journal-title":"Am J Physiol"},{"key":"2022122915250242200_cvac050-B2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1126\/science.abc8861","article-title":"Comprehensive quantification of fuel use by the failing and nonfailing human heart","volume":"370","author":"Murashige","year":"2020","journal-title":"Science"},{"key":"2022122915250242200_cvac050-B3","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1161\/CIRCULATIONAHA.115.017355","article-title":"The failing heart relies on ketone bodies as a fuel","volume":"133","author":"Aubert","year":"2016","journal-title":"Circulation"},{"key":"2022122915250242200_cvac050-B4","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1161\/01.CIR.0000023531.22727.C1","article-title":"Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-\u03b1 in pacing-induced heart failure","volume":"106","author":"Osorio","year":"2002","journal-title":"Circulation"},{"key":"2022122915250242200_cvac050-B5","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1161\/CIRCRESAHA.119.315483","article-title":"Metabolic remodeling promotes cardiac hypertrophy by directing glucose to aspartate biosynthesis","author":"Ritterhoff","year":"2020","journal-title":"Circ Res"},{"key":"2022122915250242200_cvac050-B6","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1093\/cvr\/cvp414","article-title":"Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload","volume":"86","author":"Doenst","year":"2010","journal-title":"Cardiovasc Res"},{"key":"2022122915250242200_cvac050-B7","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1161\/CIRCULATIONAHA.115.017545","article-title":"Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure","volume":"133","author":"Bedi","year":"2016","journal-title":"Circulation"},{"key":"2022122915250242200_cvac050-B8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0735-1097(02)01967-8","article-title":"Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy","volume":"40","author":"D\u00e1vila-Rom\u00e1n","year":"2002","journal-title":"J Am Coll Cardiol"},{"key":"2022122915250242200_cvac050-B9","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1161\/01.CIR.94.11.2837","article-title":"Fatty acid oxidation enzyme gene expression is downregulated in the failing heart","volume":"94","author":"Sack","year":"1996","journal-title":"Circulation"},{"key":"2022122915250242200_cvac050-B10","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1002\/jimd.12266","article-title":"Subclinical effects of long-chain fatty acid \u03b2-oxidation deficiency on the adult heart: a case-control magnetic resonance study","volume":"43","author":"Knottnerus","year":"2020","journal-title":"J Inherit Metab Dis"},{"key":"2022122915250242200_cvac050-B11","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1161\/01.CIR.100.22.2248","article-title":"Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children","volume":"100","author":"Bonnet","year":"1999","journal-title":"Circulation"},{"key":"2022122915250242200_cvac050-B12","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJM199403313301308","article-title":"Inherited Cardiomyopathies","volume":"330","author":"Kelly","year":"1994","journal-title":"N Engl J Med"},{"key":"2022122915250242200_cvac050-B13","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/0002-9149(93)91020-I","article-title":"Detection and assessment by positron emission tomography of a genetically determined defect in myocardial fatty acid utilization (long-chain acyl-coa dehydrogenase deficiency)","volume":"71","author":"Kelly","year":"1993","journal-title":"Am J Cardiol"},{"key":"2022122915250242200_cvac050-B14","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1023\/A:1012711009687","article-title":"Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy","volume":"24","author":"Bergmann","year":"2001","journal-title":"J Inherit Metab Dis"},{"key":"2022122915250242200_cvac050-B15","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1161\/CIRCIMAGING.111.963751","article-title":"Fasting-induced myocardial lipid accumulation in long-chain acyl-coa dehydrogenase knockout mice is accompanied by impaired left ventricular function","volume":"4","author":"Bakermans","year":"2011","journal-title":"Circ Cardiovasc Imaging"},{"key":"2022122915250242200_cvac050-B16","doi-asserted-by":"crossref","first-page":"5249","DOI":"10.1093\/hmg\/ddt382","article-title":"Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects","volume":"22","author":"Houten","year":"2013","journal-title":"Hum Mol Genet"},{"key":"2022122915250242200_cvac050-B17","doi-asserted-by":"crossref","first-page":"15592","DOI":"10.1073\/pnas.95.26.15592","article-title":"Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation","volume":"95","author":"Kurtz","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022122915250242200_cvac050-B18","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.bbalip.2009.05.006","article-title":"Mitochondrial long chain fatty acid \u03b2-oxidation in man and mouse","volume":"1791","author":"Chegary","year":"2009","journal-title":"Biochim Biophys Acta"},{"key":"2022122915250242200_cvac050-B19","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/labinvest.2009.86","article-title":"Cardiac hypertrophy in mice with long-chain acyl-CoA dehydrogenase or very long-chain acyl-CoA dehydrogenase deficiency","volume":"89","author":"Cox","year":"2009","journal-title":"Lab Investig"},{"key":"2022122915250242200_cvac050-B20","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/cvr\/cvt212","article-title":"Myocardial energy shortage and unmet anaplerotic needs in the fasted long-chain acyl-Co A dehydrogenase knockout mouse","volume":"100","author":"Bakermans","year":"2013","journal-title":"Cardiovasc Res"},{"key":"2022122915250242200_cvac050-B21","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","article-title":"Regulated translation initiation controls stress-induced gene expression in mammalian cells","volume":"6","author":"Harding","year":"2000","journal-title":"Mol Cell"},{"key":"2022122915250242200_cvac050-B22","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Pakos-Zebrucka","year":"2016","journal-title":"EMBO Rep"},{"key":"2022122915250242200_cvac050-B23","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: from mechanism to disease","volume":"368","author":"Costa-Mattioli","year":"2020","journal-title":"Science"},{"key":"2022122915250242200_cvac050-B24","doi-asserted-by":"crossref","first-page":"11269","DOI":"10.1073\/pnas.0400541101","article-title":"Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells","volume":"101","author":"Vattem","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022122915250242200_cvac050-B25","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S1097-2765(03)00105-9","article-title":"An integrated stress response regulates amino acid metabolism and resistance to oxidative stress","volume":"11","author":"Harding","year":"2003","journal-title":"Mol Cell"},{"key":"2022122915250242200_cvac050-B26","doi-asserted-by":"crossref","first-page":"e63326","DOI":"10.7554\/eLife.63326","article-title":"The mtorc1-mediated activation of atf4 promotes protein and glutathione synthesis downstream of growth signals","volume":"10","author":"Torrence","year":"2021","journal-title":"Elife"},{"key":"2022122915250242200_cvac050-B27","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ymgme.2012.02.009","article-title":"Acadl-SNP based genotyping assay for long-chain acyl-CoA dehydrogenase deficient mice","volume":"106","author":"Luther","year":"2012","journal-title":"Mol Genet Metab"},{"key":"2022122915250242200_cvac050-B28","doi-asserted-by":"crossref","first-page":"18443","DOI":"10.1074\/jbc.M117.800839","article-title":"Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy","volume":"292","author":"Pereyra","year":"2017","journal-title":"J Biol Chem"},{"key":"2022122915250242200_cvac050-B29","doi-asserted-by":"crossref","first-page":"100069","DOI":"10.1016\/j.jlr.2021.100069","article-title":"Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency","volume":"62","author":"Pereyra","year":"2021","journal-title":"J Lipid Res"},{"key":"2022122915250242200_cvac050-B30","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/jimd.12204","article-title":"Slc22a5 haploinsufficiency does not aggravate the phenotype of the long-chain acyl-CoA dehydrogenase KO mouse","volume":"43","author":"Ranea-Robles","year":"2020","journal-title":"J Inherit Metab Dis"},{"key":"2022122915250242200_cvac050-B31","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ymgme.2019.01.021","article-title":"Mild inborn errors of metabolism in commonly used inbred mouse strains","volume":"126","author":"Leandro","year":"2019","journal-title":"Mol Genet Metab"},{"key":"2022122915250242200_cvac050-B32","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.jchromb.2013.11.017","article-title":"A rapid, sensitive method for quantitative analysis of underivatized amino acids by liquid chromatography-tandem mass spectrometry (LC-MS\/MS)","volume":"944","author":"Le","year":"2014","journal-title":"J Chromatogr B Anal Technol Biomed Life Sci"},{"key":"2022122915250242200_cvac050-B33","doi-asserted-by":"crossref","first-page":"e62307","DOI":"10.7554\/eLife.62307","article-title":"Translation in amino-acid-poor environments is limited by tRNAGln charging","volume":"9","author":"Pavlova","year":"2020","journal-title":"Elife"},{"key":"2022122915250242200_cvac050-B34","doi-asserted-by":"crossref","first-page":"E216","DOI":"10.1152\/ajpendo.00545.2007","article-title":"Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle","volume":"295","author":"Yuan","year":"2008","journal-title":"Am J Physiol - Endocrinol Metab"},{"key":"2022122915250242200_cvac050-B35","doi-asserted-by":"crossref","first-page":"E1048","DOI":"10.1152\/ajpendo.00340.2005","article-title":"Novel application of the \u2018doubly labeled\u2019 water method: measuring CO2 production and the tissue-specific dynamics of lipid and protein in vivo","volume":"290","author":"Bederman","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022122915250242200_cvac050-B36","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1743-7075-7-31","article-title":"The application of 2H2O to measure skeletal muscle protein synthesis","volume":"7","author":"Gasier","year":"2010","journal-title":"Nutr Metab (Lond)"},{"key":"2022122915250242200_cvac050-B37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1152\/japplphysiol.00004.2014","article-title":"Chronic hindlimb suspension unloading markedly decreases turnover rates of skeletal and cardiac muscle proteins and adipose tissue triglycerides","volume":"119","author":"Bederman","year":"2015","journal-title":"J Appl Physiol"},{"key":"2022122915250242200_cvac050-B38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1083\/jcb.200408003","article-title":"Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response","volume":"167","author":"Lu","year":"2004","journal-title":"J Cell Biol"},{"key":"2022122915250242200_cvac050-B39","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1083\/jcb.201702058","article-title":"Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals","volume":"216","author":"Quir\u00f3s","year":"2017","journal-title":"J Cell Biol"},{"key":"2022122915250242200_cvac050-B40","doi-asserted-by":"crossref","first-page":"24120","DOI":"10.1074\/jbc.M201959200","article-title":"ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene","volume":"277","author":"Siu","year":"2002","journal-title":"J Biol Chem"},{"key":"2022122915250242200_cvac050-B41","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-nutr-120919-041411","article-title":"Nutrient control of mRNA translation","volume":"40:","author":"Shu","year":"2020","journal-title":"Annu Rev Nutr"},{"key":"2022122915250242200_cvac050-B42","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.metabol.2011.11.009","article-title":"Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite","volume":"61","author":"Soeters","year":"2012","journal-title":"Metabolism"},{"key":"2022122915250242200_cvac050-B43","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1126\/science.aad0489","article-title":"mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle","volume":"351","author":"Ben-Sahra","year":"2016","journal-title":"Science"},{"key":"2022122915250242200_cvac050-B44","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/16729","article-title":"Protein translation and folding are coupled by an endoplasmic- reticulum-resident kinase","volume":"397","author":"Harding","year":"1999","journal-title":"Nature"},{"key":"2022122915250242200_cvac050-B45","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0092-8674(01)00611-0","article-title":"XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor","volume":"107","author":"Yoshida","year":"2001","journal-title":"Cell"},{"key":"2022122915250242200_cvac050-B46","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1046\/j.1432-1327.1999.00780.x","article-title":"Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2\u03b1 kinase","volume":"265","author":"Berlanga","year":"1999","journal-title":"Eur J Biochem"},{"key":"2022122915250242200_cvac050-B47","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.1128\/MCB.22.19.6681-6688.2002","article-title":"The GCN2 eIF2\u03b1 kinase is required for adaptation to amino acid deprivation in mice","volume":"22","author":"Zhang","year":"2002","journal-title":"Mol Cell Biol"},{"key":"2022122915250242200_cvac050-B48","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.1128\/MCB.15.8.4497","article-title":"The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids","volume":"15","author":"Wek","year":"1995","journal-title":"Mol Cell Biol"},{"key":"2022122915250242200_cvac050-B49","doi-asserted-by":"crossref","first-page":"4946","DOI":"10.1073\/pnas.1813352116","article-title":"Activation of GCN2 by the ribosomal P-stalk","volume":"116","author":"Inglis","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022122915250242200_cvac050-B50","doi-asserted-by":"crossref","first-page":"e14295","DOI":"10.7554\/eLife.14295","article-title":"Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation","volume":"5","author":"Ishimura","year":"2016","journal-title":"Elife"},{"key":"2022122915250242200_cvac050-B51","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1097-2765(00)00028-9","article-title":"Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain","volume":"6","author":"Dong","year":"2000","journal-title":"Mol Cell"},{"key":"2022122915250242200_cvac050-B52","doi-asserted-by":"crossref","first-page":"e30952","DOI":"10.7554\/eLife.30952","article-title":"Transcriptomic and proteomic landscape of mitochondrial dysfunction reveals secondary coenzyme Q deficiency in mammals","volume":"6","author":"K\u00fchl","year":"2017","journal-title":"Elife"},{"key":"2022122915250242200_cvac050-B53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s00395-021-00853-z","article-title":"Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant","volume":"116","author":"Jiang","year":"2021","journal-title":"Basic Res Cardiol"},{"key":"2022122915250242200_cvac050-B54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1472-6793-9-23","article-title":"Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure","volume":"9","author":"Galindo","year":"2009","journal-title":"BMC Physiol"},{"key":"2022122915250242200_cvac050-B55","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1016\/j.cell.2016.11.013","article-title":"Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder","volume":"167","author":"T\u0103rlungeanu","year":"2016","journal-title":"Cell"},{"key":"2022122915250242200_cvac050-B56","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.cmet.2014.02.004","article-title":"Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart","volume":"19","author":"Dogan","year":"2014","journal-title":"Cell Metab"},{"key":"2022122915250242200_cvac050-B57","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.cmet.2019.08.019","article-title":"Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions","volume":"30","author":"Forsstr\u00f6m","year":"2019","journal-title":"Cell Metab"},{"key":"2022122915250242200_cvac050-B58","doi-asserted-by":"crossref","first-page":"e49178","DOI":"10.7554\/eLife.49178","article-title":"Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell","volume":"9","author":"Mick","year":"2020","journal-title":"Elife"},{"key":"2022122915250242200_cvac050-B59","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.freeradbiomed.2018.10.445","article-title":"GCN2 deficiency ameliorates cardiac dysfunction in diabetic mice by reducing lipotoxicity and oxidative stress","volume":"130","author":"Feng","year":"2019","journal-title":"Free Radic Biol Med"},{"key":"2022122915250242200_cvac050-B60","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1161\/HYPERTENSIONAHA.113.02313","article-title":"Loss of the eukaryotic initiation factor 2\u03b1 kinase general control nonderepressible 2 protects mice from pressure overload-induced congestive heart failure without affecting ventricular hypertrophy","volume":"63","author":"Lu","year":"2014","journal-title":"Hypertension"},{"key":"2022122915250242200_cvac050-B61","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41586-020-2078-2","article-title":"Mitochondrial stress is relayed to the cytosol by an OMA1\u2013DELE1\u2013HRI pathway","volume":"579","author":"Guo","year":"2020","journal-title":"Nature"},{"key":"2022122915250242200_cvac050-B62","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41586-020-2076-4","article-title":"A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol","volume":"579","author":"Fessler","year":"2020","journal-title":"Nature"},{"key":"2022122915250242200_cvac050-B63","doi-asserted-by":"crossref","first-page":"e2022120118","DOI":"10.1073\/pnas.2022120118","article-title":"Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction","volume":"118","author":"Condon","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022122915250242200_cvac050-B64","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.molcel.2018.07.029","article-title":"PKR senses nuclear and mitochondrial signals by interacting with endogenous double-stranded RNAs","volume":"71","author":"Kim","year":"2018","journal-title":"Mol Cell"},{"key":"2022122915250242200_cvac050-B65","doi-asserted-by":"crossref","first-page":"5519","DOI":"10.1016\/S0021-9258(18)53351-2","article-title":"Purification of glutamine tRNA synthetase from Saccharomyces cerevisiae. A monomeric aminoacyl-tRNA synthetase with a large and dispensable NH2- terminal domain","volume":"268","author":"Ludmerer","year":"1993","journal-title":"J Biol Chem"},{"key":"2022122915250242200_cvac050-B66","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0005-2787(80)90221-X","article-title":"The glutaminyl-transfer RNA synthetase of Escherichia coli. Purification, structure and function relationship","volume":"607","author":"Kern","year":"1980","journal-title":"Biochim Biophys Acta"},{"key":"2022122915250242200_cvac050-B67","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0076-6879(85)13011-9","article-title":"Glutaminyl-tRNA synthetase of Escherichia coli","volume":"113","author":"Hoben","year":"1985","journal-title":"Methods Enzymol"},{"key":"2022122915250242200_cvac050-B68","doi-asserted-by":"crossref","first-page":"e10575","DOI":"10.7554\/eLife.10575","article-title":"Mitochondrial dysfunction remodels one-carbon metabolism in human cells","volume":"5","author":"Bao","year":"2016","journal-title":"Elife"},{"key":"2022122915250242200_cvac050-B69","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.cmet.2016.01.019","article-title":"Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism","volume":"23","author":"Nikkanen","year":"2016","journal-title":"Cell Metab"},{"key":"2022122915250242200_cvac050-B70","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1161\/CIRCRESAHA.118.312017","article-title":"Metabolic coordination of physiological and pathological cardiac remodeling","volume":"123","author":"Gibb","year":"2018","journal-title":"Circ. Res"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvac050\/43513916\/cvac050.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/118\/16\/3198\/48443860\/cvac050.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/118\/16\/3198\/48443860\/cvac050.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T10:28:15Z","timestamp":1672309695000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/118\/16\/3198\/6564536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,7]]},"references-count":70,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,4,7]]},"published-print":{"date-parts":[[2022,12,29]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvac050","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.13.443905","asserted-by":"object"}]},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,4,7]]}}}