TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Schumann, Anke
A1  - Schaller, Kristin
A1  - Belche, Véronique
A1  - Cybulla, Markus
A1  - Grünert, Sarah C.
A1  - Moers, Nicolai
A1  - Sass, Jörn O.
A1  - Kaech, Andres
A1  - Hannibal, Luciana
A1  - Spiekerkoetter, Ute
T1  - Defective lysosomal storage in Fabry Disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells
JF  - Journal of Inherited Metabolic Disease
N2  - 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.
KW  - altered mitochondrial homeostasis
KW  - autophagy
KW  - Fabry disease
KW  - mitochondrial biogenesis
KW  - renal tubular cells
KW  - sirtuins
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-53487
SN  - 0141-8955
SS  - 0141-8955
U6  - https://doi.org/10.1002/jimd.12373
DO  - https://doi.org/10.1002/jimd.12373
PM  - 33661535
VL  - 44
SP  - 1039
EP  - 1050
PB  - John Wiley & Sons Ltd
CY  - Hoboken, NJ, USA
ER  -