Abstract
Cystinosis is a systemic genetic disease caused by a lysosomal transport deficiency accumulating cystine in the lysosomes of almost all tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are still obscures. Adenylate kinase, along with creatine kinase, is responsible for the enzymatic phosphotransfer network, crucial for energy homeostasis. Taking into account that cystine is known to inhibit creatine kinase activity, the two enzymes have thiol groups, and the strong interaction between the two activities, our main objective was to investigate the effect of cystine on adenylate kinase activity in the brain cortex of Wistar rats. For the in vivo studies, the animals were injected twice a day with 1.6 μmol/g body weight of cystine dimethylester and/or 0.46 μmol/g body weight of cysteamine from the 25th to the 29th postpartum day and sacrificed after 12 h. Cystine inhibited the enzyme activity in vitro in a concentration dependent way, whereas cysteamine prevented the inhibition. Adenylate kinase activity was found diminished in the brain cortex of rats loaded with cystine dimethylester and co-administration of cysteamine prevented the diminution of the enzyme activity. Considering that adenylate kinase together with creatine kinase is crucial for energy homeostasis, the release of cystine from lysosomes with consequent enzymes inhibition could impair energy homeostasis, contributing to tissue damage in patients with cystinosis.
Similar content being viewed by others
References
Ben-Nun A, Bashan N, Potashnik R, Cohen-Luria R, Moran A (1993) Cystine loading induces Fanconi’s syndrome in rats: in vivo and vesicle studies. Am. J. Physiol. 265:839–844
Ben-Nun A, Bashan N, Potashnik R, Cohen-luria R, Moran A (1992) Cystine dimethyl ester reduces the forces driving sodium-dependent transport in Llc-Pk1 cells. Am. J. Physiol. 263:C516–C520
Burlacu A, Jinga V, Gafencu AV, Simionescu M (2001) Severity of oxidative stress generates different mechanisms of endothelial cell death. Cell Tissue Res. 306:409–416
Çcetinkaya I, Schlatter E, Hirsch JR, Herter P, Harms E, Kleta R (2002) Inhibition of Na+-dependent transporters in cystine-loaded human renal cells: electrophysiological studies on the Fanconi syndrome of cystinosis. J. Am. Soc. Nephrol. 13:2085–2093
Coor C, Salmon RF, Quigley R, Marver D, Baum M (1991) Role of adenosine- triphosphate (ATP) and Na+, K+ -ATPase in the inhibition of proximal tubule transport with intracellular cystine loading. J. Clin. Invest. 87:955–961
Das, U.N. (2006). Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule. Med. Sci. Monit. 12: RA79-84
Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J. Exp. Biol. 206:2039–2047
Dzeja PP, Bortolon R, Perez-Terzic C, Holmuhamedov EL, Terzic A (2002) Energetic communication between mitochondria and nucleus directed by catalyzed phosphotransfer. Proc. Natl. Acad. Sci. USA 99:10156–10161
Dzeja PP, Vitkevicius KT, Redfield MM, Burnettm JC, Terzic A (1999) Adenylate Kinase–Catalyzed Phosphotransfer in the Myocardium: Increased Contribution in Heart Failure. Circ. Res. 84:1137–1143
Feksa LR, Cornelio A, Dutra-Filho CS, Wyse ATS, Wajner M, Wannmacher CMD (2004) Inhibition of pyruvate kinase activity by cystine in brain cortex of rats. Brain. Res. 1012:93–100
Fleck RMM, Rodrigues-Junior V, Giacomazzi J, Parissoto D, Dutra-Filho CS, Wyse ATS, Wajner M, Wannmacher CMD (2005) Cysteamine prevents and reverses the inhibition of creatine kinase activity caused by cystine in rat brain cortex. Neurochem. Int. 46:391–397
Foreman JW, Benson LL, Wellons M, Avner ED, Sweeney W, Nissim I, Nissim I (1995) Metabolic studies of rat renal tubule cells loaded with cystine: the cystine dimethylester model of cystinosis. J. Am. Soc. Nephrol. 6:269–272
Foreman JW, Bowring MA, Lee J, States B, Segal S (1987) Effect of cystine dimethyl ester on renal solute handling and isolated renal tubule transport in the rat: A new model Fanconi syndrome. Metab. 36:1185–1191
Gahl WA (2003) Early oral cysteamine therapy for nephropathic cystinosis. Eur. J. Pediatr. 162(1):38–41
Gahl WA, Thoene JG, Schneider JA (2002) Cystinosis. N. Engl. J. Med. 347:111–121
Gahl WA, Thoene JG, Schneider JA (2001) Cystinosis: a disorder of lysosomal membrane transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic & Molecular Bases of Inherited Diseases. McGraw- Hill, New York, pp 5085–5108
Gonzalez FB, Llesuy S, Boveris A (1991) Hydroperoxide initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radic. Biol. Med. 10:93–100
Kessler A, Biasibetti M, da Silva Melo DA, Wajner M, Dutra-Filho CS, Wyse ATS, Wannmacher CMD (2008) Antioxidant Effect of Cysteamine in Brain Cortex of Young Rats. Neurochem. Res. 33:737–744
Laube GF, Shah V, Stewart VC, Hargreaves IP, Haq MR, Heales SJ, van’t Hoff WG (2006) Glutathione depletion and increased apoptosis rate in human cystinotic proximal tubular cells. Pediatr. Nephrol. 21:503–509
Leech NL, Barrett KC, Morgan GA (2005) SPSS for intermediate statistics. Use and interpretation, Lawrence Erlbaum Associates Publishers, London, pp 46–62
Levtchenko EN, Wilmer MJG, Janssen AJM, Koenderink JB, Visch AJ, Willems PH, Graaf-Hess A, Blom HJ, van den Heuvel LP, Monnens LA (2006) Decreased ATP content and intact mitochondrial energy generating capacity in human cystinotic fibroblasts. Pediatr. Res. 59:287–292
Llesuy SF, Milei J, Molina H (1985) Comparison of lipid peroxidation and myocardial damage induced by adriamycin and 40-epiadriamycin in mice. Tumori. 71(3):241–249
Lloyd JB (1986) Disulphide reduction in lysosomes. The role of cysteine. Biochem. J. 237(1):271–272
Lowry OH, Rosebrough NJ, Farr AL (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275
Oliveira PRP, Rodrigues-Junior V, Rech VC, Wannmacher CMD (2007) Cystine Inhibits Creatine Kinase Activity in Pig Retina. Arch. Med. Res. 38:164–169
Oliver IT (1955) A Spectrophotometric Method for the Determination of Creatine Phosphokinase and Myokinase. Biochem. J. 61(1):116–122
Park MA, Thoene JG (2005) Potential role of apoptosis in development of the cystinotic phenotype. Pediatr. Nephrol. 20:441–446
Pisoni RL, Park GY, Velilla VQ, Thoene JG (1995) Detection and characterization of a transport system mediating cysteamine entry into human fibroblast lysosomes. Specificity for aminoethylthiol and aminoethylsulfide derivatives. J. Biol. Chem. 270:1179–1184
Price NC, Cohn M, Schirmer RH (1975) Fluorescent and Spin Label Probes of the Environments of the Sulfhydryl Groups of Porcine Muscle Adenylate Kinase. J. Biol. Chem. 250:644–652
Pucar D, Janssen E, Dzeja PP, Juranic N, Macura S, Wieringa B, Terzic A (2000) Compromised Energetics in the Adenylate Kinase AK1 Gene Knockout Heart under Metabolic Stress. J. Biol. Chem. 275:41424–41429
Rech VC, Feksa LR, Amaral MFA, Koch GW, Wajner M, Dutra-Filho CS, Wyse ATS, Wannmacher CMD (2007) Promotion of oxidative stress in kidney of rats loaded with cystine dimethyl ester. Pediatr. Nephro. L 22:1121–1128
Rosa TG, Wyse ATS, Wajner M, Wannmacher CMD (2004) Cysteamine prevents and reverses the inhibition of pyruvate kinase activity caused by cystine in rat heart. Biochim. Biophys. Acta 1689:114–119
Salmon RF, Baum M (1990) Intracellular Cystine Loading Inhibits Transport in the Rabbit Proximal Convoluted Tubule. J. Clin. Invest. 85:340–344
Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore S, Callen D, Gribouval O, Broyer M, Bates G, van’t Hoff W, Antignac C (1998) A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat. Genet. 18:319–324
Weeds AG, Noda L (1968) Amino Acid Sequences around the Thiol Groups of Myokinase. Biochem J. 107:311–312
Willemoes M, Kilstrup M (2005) Nucleoside triphosphate synthesis catalysed by Adenylate Kinase is ADP dependent. Arch. Biochem. Biophys. 444:195–199
Wilmer MJ, Willems PH, Verkaart S, Visch HJ, de Graaf-Hess A, Blom HJ, Monnens LA, van den Heuvel LP, Levtchenko EN (2007) Cystine dimethylester model of cystinosis: still reliable? Pediatr. Res. 62:151–5
Wilmer MJ, de Graaf-Hess A, Blom HJ, Dijkman HB, Monnens LA, van den Heuvel LP, Levtchenko EM (2005) Elevated oxidized glutathione in cystinotic proximal tubular epithelial cells. Biochem. Biophys. Res. Commun. 337:610–614
Acknowledgements
This work was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e tecnológico (CNPq-Brazil), Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS, RS-Brazil), Programa de Núcleos de Excelência (PRONEX-CNPq /FAPERGS -Brazil) and Rede instituto Brasileiro de Neurociências (FINEP /IBN-Net #01.06.0842-00)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Casagrande Figueiredo, V., Feksa, L.R. & Wannmacher, C.M.D. Cysteamine prevents inhibition of adenylate kinase caused by cystine in rat brain cortex. Metab Brain Dis 24, 723–731 (2009). https://doi.org/10.1007/s11011-009-9141-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-009-9141-x