{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:31:16Z","timestamp":1790605876501,"version":"4.1.0"},"reference-count":85,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T00:00:00Z","timestamp":1596153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL69071"],"award-info":[{"award-number":["R01 HL69071"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL116906"],"award-info":[{"award-number":["HL116906"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AHA17GRNT33670495"],"award-info":[{"award-number":["AHA17GRNT33670495"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL109209"],"award-info":[{"award-number":["R01HL109209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1 TR002535"],"award-info":[{"award-number":["UL1 TR002535"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL147064"],"award-info":[{"award-number":["R01HL147064"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["14-CVD 03"],"award-info":[{"award-number":["14-CVD 03"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["MDA67944"],"award-info":[{"award-number":["MDA67944"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes\u2019 energetic balance and NAD+\/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.<\/jats:p>","DOI":"10.3390\/jcm9082457","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T07:45:57Z","timestamp":1596440757000},"page":"2457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8633-5458","authenticated-orcid":false,"given":"Giorgia","family":"Del Favero","sequence":"first","affiliation":[{"name":"Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, W\u00e4hringer Stra\u00dfe, 38\u201340, 1090 Vienna, Austria"},{"name":"Core Facility Multimodal Imaging University of Vienna. W\u00e4hringer Stra\u00dfe, 38\u201340, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2251-7786","authenticated-orcid":false,"given":"Alois","family":"Bonifacio","sequence":"additional","affiliation":[{"name":"Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teisha J.","family":"Rowland","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Gao","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute and Adult Medical Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhua","family":"Song","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute and Adult Medical Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3864-658X","authenticated-orcid":false,"given":"Valter","family":"Sergo","sequence":"additional","affiliation":[{"name":"Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric D.","family":"Adler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of California San Diego, 9500 Gilman Drive, Biomedical Research Facility, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1116-2286","authenticated-orcid":false,"given":"Luisa","family":"Mestroni","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute and Adult Medical Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8933-5071","authenticated-orcid":false,"given":"Orfeo","family":"Sbaizero","sequence":"additional","affiliation":[{"name":"Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9043-0810","authenticated-orcid":false,"given":"Matthew R. G.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute and Adult Medical Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/35022604","article-title":"Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease)","volume":"406","author":"Nishino","year":"2000","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.mam.2006.08.005","article-title":"Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy","volume":"27","author":"Eskelinen","year":"2006","journal-title":"Mol. Asp. 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