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

Year: 2020
Type: article
Abstract: 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.
DOI: 10.3390/jcm9082457
Authors: Giorgia Del Favero, Alois Bonifacio, Teisha J. Rowland, Shanshan Gao, Kunhua Song, Valter Sergo, Eric D. Adler, Luisa Mestroni, Orfeo Sbaizero, Matthew R. G. Taylor
Language: English
Open Access status: gold
Estimated APC paid: $2,324
Funders: Muscular Dystrophy Association, Fondation Leducq, Universität Wien, National Institutes of Health, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Awards: Whole genome DNA sequencing to identify novel genes in dilated cardiomyopathy, Genetics, Mechanisms and Clinical Phenotypes of Arrhythmogenic Cardiomyopathy, Molecular Genetics, Pathogenesis and Protein-Replacement Therapy in Arrhythmogenic Cardiomyopathy, G5147404460, Cardiomyocyte phenotype and mechanotransduction in Filamin C gene variants causing arrhythmogenic cardiomyopathy, G5299480414, Colorado Clinical and Translational Sciences Institute, Colorado Clinical and Transational Sciences Institute, Molecular Epidemiology of Dilated Cardiomyopath
OpenAlex ID: W3046457836
FWCI: 0.973
Cites: 85
Cited by: 21
Related to: 10