Titel
Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes
Autor*in
Teisha J. Rowland
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder
... show all
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.
Stichwort
Danon diseaseLAMP-2 deficiencycardiac fibrosismulti-omics profilingmitochondrial aging phenotypecell biomechanics
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Journal of Clinical Medicine
Band
9
Ausgabe
8
ISSN
2077-0383
Erscheinungsdatum
2020
Publication
MDPI AG
Erscheinungsdatum
2020
Zugänglichkeit
Rechte
Rechteangabe
© 2020 by the authors
Universität Wien | Universitätsring 1 | 1010 Wien | T
+43-1-4277-0