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Open AccessArticle

Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

1
Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße, 38–40, 1090 Vienna, Austria
2
Core Facility Multimodal Imaging University of Vienna. Währinger Straße, 38–40, 1090 Vienna, Austria
3
Department of Engineering and Architecture, University of Trieste, 34127 Trieste, Italy
4
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
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Cardiovascular Institute and Adult Medical Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Department of Medicine, Division of Cardiology, University of California San Diego, 9500 Gilman Drive, Biomedical Research Facility, La Jolla, CA 92093, USA
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(8), 2457; https://doi.org/10.3390/jcm9082457
Received: 14 June 2020 / Revised: 15 July 2020 / Accepted: 21 July 2020 / Published: 31 July 2020
(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)
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’ 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. View Full-Text
Keywords: Danon disease; LAMP-2 deficiency; cardiac fibrosis; multi-omics profiling; mitochondrial aging phenotype; cell biomechanics Danon disease; LAMP-2 deficiency; cardiac fibrosis; multi-omics profiling; mitochondrial aging phenotype; cell biomechanics
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MDPI and ACS Style

Del Favero, G.; Bonifacio, A.; Rowland, T.J.; Gao, S.; Song, K.; Sergo, V.; Adler, E.D.; Mestroni, L.; Sbaizero, O.; Taylor, M.R.G. Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes. J. Clin. Med. 2020, 9, 2457. https://doi.org/10.3390/jcm9082457

AMA Style

Del Favero G, Bonifacio A, Rowland TJ, Gao S, Song K, Sergo V, Adler ED, Mestroni L, Sbaizero O, Taylor MRG. Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes. Journal of Clinical Medicine. 2020; 9(8):2457. https://doi.org/10.3390/jcm9082457

Chicago/Turabian Style

Del Favero, Giorgia; Bonifacio, Alois; Rowland, Teisha J.; Gao, Shanshan; Song, Kunhua; Sergo, Valter; Adler, Eric D.; Mestroni, Luisa; Sbaizero, Orfeo; Taylor, Matthew R.G. 2020. "Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes" J. Clin. Med. 9, no. 8: 2457. https://doi.org/10.3390/jcm9082457

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