Decreased intracellular ATP content and intact mitochondrial energy generating capacity in human cystinotic fibroblasts.
Cystinosis is an autosomal recessive lysosomal storage disorder caused by a defect in the lysosomal cystine carrier cystinosin. Cystinosis is the most common cause of inherited Fanconi syndrome leading to renal failure, in which the pathogenesis is still enigmatic. Based on studies of proximal tubules loaded with cystine dimethyl ester (CDME), altered mitochondrial adenosine triphosphate (ATP) production was proposed to be an underlying pathologic mechanism. Thus far, however, experimental evidence supporting this hypothesis in humans is lacking. In this study, energy metabolism was extensively investigated in primary fibroblasts derived from eight healthy subjects and eight patients with cystinosis. Patient's fibroblasts accumulated marked amounts of cystine and displayed a significant decrease in intracellular ATP content. Remarkably, overall energy-generating capacity, activity of respiratory chain complexes, ouabain-dependent rubidium uptake reflecting Na,K-ATPase activity, and bradykinin-stimulated mitochondrial ATP production were all normal in these cells. In conclusion, the data presented demonstrate that mitochondrial energy-generating capacity and Na,K-ATPase activity are intact in cultured cystinotic fibroblasts, thus questioning the idea of altered mitochondrial ATP synthesis as a keystone for the pathogenesis of cystinosis.
Levtchenko
Elena N
EN
Department of Pediatrics, Radboud University Nijmegen Medical Center, The Netherlands. e.levtchenko@cukz.umcn.nl
Wilmer
Martijn J G
MJ
Janssen
Antoon J M
AJ
Koenderink
Jan B
JB
Visch
Henk-Jan
HJ
Willems
Peter H G M
PH
de Graaf-Hess
Adriana
A
Blom
Henk J
HJ
van den Heuvel
Lambertus P
LP
Monnens
Leo A
LA
D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism*; D016022:Case-Control Studies; D003554:Cystinosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004579:Electron Transport; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase