Volltext-Downloads (blau) und Frontdoor-Views (grau)

Defective lysosomal storage in Fabry Disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells

  • Fabry disease (FD) is an X‐linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha‐galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life‐threatening long‐term complications. The complete pathophysiology of chronic kidney disease (CKD) in FD and the role of tubular involvement for its progression are unclear. We established human renal tubular epithelial cell lines from the urine of male FD patients and male controls. The renal tubular system is rich in mitochondria and involved in transport processes at high energy costs. Our studies revealed fragmented mitochondria with disrupted cristae structure in FD patient cells. Oxidative stress levels were elevated and oxidative phosphorylation was up‐regulated in FD pointing at enhanced energetic needs. Mitochondrial homeostasis and energy metabolism revealed major changes as evidenced by differences in mitochondrial number, energy production and fuel consumption. The changes were accompanied by activation of the autophagy machinery in FD. Sirtuin1, an important sensor of (renal) metabolic stress and modifier of different defense pathways, was highly expressed in FD. Our data show that lysosomal FD impairs mitochondrial function and results in severe disturbance of mitochondrial energy metabolism in renal cells. This insight on a tissue‐specific level points to new therapeutic targets which might enhance treatment efficacy.

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar Check availability

Statistics

Show usage statistics
Metadaten
Document Type:Article
Language:English
Author:Anke Schumann, Kristin Schaller, Véronique Belche, Markus Cybulla, Sarah C. Grünert, Nicolai Moers, Jörn O. Sass, Andres Kaech, Luciana Hannibal, Ute Spiekerkoetter
Parent Title (English):Journal of Inherited Metabolic Disease
Volume:44
First Page:1039
Last Page:1050
ISSN:0141-8955
URN:urn:nbn:de:hbz:1044-opus-53487
DOI:https://doi.org/10.1002/jimd.12373
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=33661535
Publisher:John Wiley & Sons Ltd
Place of publication:Hoboken, NJ, USA
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2021/03/04
Note:
© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License.
Note:
This work wassupported in parts by the Center for Inborn Errors of Metabo-lism, Freiburg Center for Rare Diseases and by the program“FH Zeit für Forschung 2016”by the Ministry of Culture andScience of the German State of North Rhine-Westphalia(KETOplus, 005-1703-0016), to JOS. This work was supportedby the Annual Research Award (2019) of the German Societyfor Pediatric Metabolic Diseases (Arbeitsgemeinschaft fürpädiatrische Stoffwechselstörungen [APS]) to AS and the“Else Kröner-Fresenius-Stiftung”(2016_Kolleg.03) to US. Theauthors would like to thank the patients and healthy volun-teers for their participation. Open Access funding enabledand  organized  by  Projekt  DEAL.  WOA  Institution:UNIVERSITATSKLINIKUM FREIBURG.
Keyword:Fabry disease; altered mitochondrial homeostasis; autophagy; mitochondrial biogenesis; renal tubular cells; sirtuins
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Projects:KETOplus - Ketonkörper: Mehr als nur Energieträger! (DE/MKW NRW/005-1703-0016)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2021/03/06
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International