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

Abstract

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 upregulated 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.

α-Galactosidase a Deficiency in Fabry Disease Leads to Extensive Dysregulated Cellular Signaling Pathways in Human Podocytes

“…Gb 3 accumulation further seems to increase pH in lysosomes, requiring an increased ATPeV expression for re-acidification. This process requires high amounts of ATP, which in turn might increase metabolic stress, potentially explaining the dysregulated proteins involved in oxidative phosphorylation as well as mitochondrial stress, which were also previously identified [ 15 ]. Furthermore, increased clathrin expression points toward increased endocytosis as well as increased protein synthesis followed by intracellular trafficking toward lysosomes.…”

“…A recent study demonstrated major metabolic alterations in AGAL-deficient tubular cells, severely affecting renal energy metabolism and underlining their role in chronic kidney disease (CKD) progression [ 15 ]. In addition, in urine-derived primary cells of FD patients, the lack of AGAL and constant accumulation of Gb 3 leads to a dysregulation of molecular pathways including disturbed autophagy and inflammation [ 6 ].…”

Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria

“…FD is a PA-unrelated metabolic disorder leading to CKD, on which we recently performed analog studies. 17 Principal component analysis for intracellular and extracellular metabolites revealed distinct clustering of healthy control, PA and FD patient cells in both compartments (Figure 7A-F). While PA and FD share metabolic characteristics with the healthy control group (overlap between ellipses centered around their respective mean values), lactate, MMA, alphaketoglutarate, sulfur-species with antioxidant roles and intermediates of FAO contribute most prominently to the distinct metabolic clustering of the three groups.…”

“…11 Mitochondrial dysfunction and defective mitochondrial priming for mitophagy have been associated to CKD in methylmalonic aciduria. 17 Based on the hypothesis that a similar mechanism might be underlying CKD in PA, we investigated human renal epithelial cells of healthy controls and PA patients. The cells were cultivated in medium containing high glucose (normal treatment, NT), low glucose and high protein (HP), and low glucose and isoleucine/valine (I/V), respectively, to simulate the effects of potentially toxic protein and amino acid exposure.…”

“…Onset and progression of CKD in MMUT have been related to the severity of the enzymatic defect and high concentrations of methylmalonic acid (MMA), the biochemical hallmark allowing differentiation between PA and MMUT 11 . Mitochondrial dysfunction and defective mitochondrial priming for mitophagy have been associated to CKD in methylmalonic aciduria 17 …”