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Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes

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Abstract

Changes in key enzymes of oxidative metabolism at the mitochondrial level are known to be associated with the aging process, apoptosis, and many diseases. Considering the risk of acquiring a myelodysplastic syndrome (MDS) with age, the aim of this study was to quantify mRNA synthesis of the carnitine palmitoyltransferases (CPT1 and CPT2), carnitine acetyltransferase (CRAT), human specific microsomal CPT, and OCTN2 (organic cation transporter) in mononuclear cells of healthy humans of different age groups and MDS patients. Using quantitative reverse transcriptase real-time PCR we compared mRNA synthesis of the above mentioned enzymes in mononuclear cells from peripheral blood of 23 healthy persons (mean age 45 years), 9 blood and 22 bone marrow samples of 31 MDS patients with varying proportions of apoptotic cells (mean age 78 years), and blood samples of 30 age-matched controls. In addition, plasma carnitine levels were determined. Compared to younger adults, there was a 50% downregulation of CPT1 in elderly persons and in MDS patients. Reduction in CRAT, CPT 2, and OCTN2 was more than 85%. Reduction in microsomal CPT was more pronounced in MDS patients than in age-matched controls (96% vs. 43%). In MDS bone marrow cells there was a negative correlation of CPT1 and CRAT with the relative proportion of apoptotic cells. Plasma carnitine values were similar in all groups. The described reduction in transcription of different genes in blood cells which is well known in different tissues may reflect a systemic signaling process, associated with aging, apoptosis, and MDS.

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Abbreviations

CACT :

Carnitine acylcarnitine translocase

CoA :

Coenzyme A

CPT :

Carnitine palmitoyltransferase

CRAT :

Carnitine acetyltransferase

MDS :

Myelodysplastic syndromes

MNC :

Mononuclear cells

PDH :

Pyruvate dehydrogenase

RTQPCR :

Quantitative reverse transcriptase real-time polymerase chain reaction

References

  1. Greenberg PL (1998) Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment. Leuk Res 22:1123–1136

    Article  CAS  PubMed  Google Scholar 

  2. Bouscary D, De Vos J, Guesnu M, Jondeau K, Viguier F, Melle J, Picard F, Dreyfus F, Fontenay-Roupie M (1997) Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia 11:839–884

    Article  CAS  PubMed  Google Scholar 

  3. Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A (2000) The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukaemia secondary to MDS. Blood 96:3932–3938

    CAS  PubMed  Google Scholar 

  4. Paumen MB, Ishida Y, Han H, Muramatsu M, Eguchi Y, Tsujimoto Y, Honjo T (1997) Direct interaction of the mitochondrial membrane protein carnitine palmitoyltransferase I with Bcl-2. Biochem Biophys Res Commun 231:523–524

    Article  CAS  PubMed  Google Scholar 

  5. McGarry JD (2001) Travels with carnitine palmitoyltransferase I. From liver to germ cell with stops in between. Biochem Soc Trans 29:241–245

    Article  CAS  PubMed  Google Scholar 

  6. Murthy MS, Pande SV (1994) A stress-regulated protein, GRP58, a member of thioredoxin superfamily, is a carnitine palmitoyltransferase isoenzyme. Biochem J 304:31–34

    CAS  PubMed  Google Scholar 

  7. Ramsay RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546:21–43

    Article  CAS  PubMed  Google Scholar 

  8. Kerner J, Turkaly PJ, Minkler PE, Hoppel CL (2001) Aging skeletal muscle mitochondria in the rat: decreased uncoupling protein-3 content. Am J Physiol Endocrinol Metab 281:E1054–1062

    CAS  PubMed  Google Scholar 

  9. Dettke M, Greinix HT, Kalhs P, Kuhrer I, Worel N, Hocker P (2001) Kinetics of PBPC mobilization by cyclophosphamide, as compared with that by epirubicin/paclitaxel followed by G-CSF support: implications for optimal timing of PBPC harvest. Transfusion 41:681–686

    Article  CAS  PubMed  Google Scholar 

  10. Karlic H, Louda N, Pfeilstöcker M, Keil F, Lohninger A, Pittermann E, Paukovits J (2001) Effect of the hemoregulatory peptide (pEEDCK)2 (pyroGlu-Glu-Asp-Cys-Lys)2 and MIP-1α is reduced in bone marrow cultures from patients with chronic myeloid leukemia (CML). Stem Cells 19:321–328

    CAS  PubMed  Google Scholar 

  11. Weghofer M, Karlic H, Haslberger A (2001) Quantitative analysis of immune-mediated stimulation of tumor necrosis factor-alpha in macrophages measured at the level of mRNA and protein synthesis. Ann Hematol 80:733–736

    CAS  PubMed  Google Scholar 

  12. Karlic H, Lohninger S, Koeck T, Lohninger A (2002) Dietary L-carnitine stimulates mitochondrial carnitine acyltransferases in the liver of aged rats. J Histochem Cytochem 50:205–212

    CAS  PubMed  Google Scholar 

  13. Nösslinger T, Reisner R, Koller E, Grüner H, Tüchler H, Nowotny H, Pittermann, E, Pfeilstöcker M (2001) Myelodysplastic syndromes, from French-American-British to World Health organization: comparison on 431 unselected patients from a single institution. Blood 98:2935–2941

    PubMed  Google Scholar 

  14. Cook GA, Edwards TL, Jansen MS, Bahouth SW, Wilcox HG, Park EA (2001) Differential regulation of carnitine palmitoyltransferase-I gene isoforms (CPT-I alpha and CPT-I beta) in the rat heart. J Mol Cell Cardiol 33:17–32

    Article  Google Scholar 

  15. Magri F, Muzzoni B, Cravello L, Fioravanti M, Busconi L, Camozzi D, Vignati G, Ferrari E (2002) Thyroid function in physiological aging and in centenarians: possible relationships with some nutritional markers. Metabolism 51:105–109

    Article  CAS  PubMed  Google Scholar 

  16. Louet JF, Le May C, Pegorier JP, Decaux JF, Girard J (2001) Regulation of liver carnitine palmitoyltransferase I gene expression by hormones and fatty acids. Biochem Soc Trans 29:310–316

    Article  CAS  PubMed  Google Scholar 

  17. Leij FR van der, Huijkman NC, Boomsma C, Kuipers JR, Bartelds B (2000) Genomics of the human carnitine acyltransferase genes. Mol Genet Metab 71:139–153

    Article  PubMed  Google Scholar 

  18. Brandt JM, Djouadi F, Kelly DP (1998) Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem 273:23786–23792

    CAS  PubMed  Google Scholar 

  19. Lohninger A, Agu CA, Hofbauer R, Hissel H, Karlic H (2002) Carnitine and transcription of carnitine palmitoyltransferases—in vitro and in vivo studies. Lipoproteinmetabolismus und Atheroskleroseprävention. Wissenschaftliche Skripten, Zwickau (ISBN: 3-928921-73-8), pp 113–122

  20. Tamai I, China K, Sai Y, Kobayshi D, Nezu J, Kawahara E, Tsuji A (2001) Na+- coupled transport of L-carnitine via high affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim Biophys Acta 1512:273–284

    Article  CAS  PubMed  Google Scholar 

  21. Pfeilstöcker M, Karlic H, Nösslinger T, Tüchler H, Lohninger A, Pittermann E (2002) Assessment of growth and differentiation processes in myelodysplastic syndromes by PCR analysis of Galpha16 and 5'-lipoxygenase. Ann Hematol 81:632–640

    Article  PubMed  Google Scholar 

  22. Gupta S (2000) Molecular and biochemical pathways of apoptosis in lymphocytes from aged humans. Vaccine 18:1596–1601

    Article  CAS  PubMed  Google Scholar 

  23. Mutomba MC, Yuan H, Konyavko M, Adachi S, Yokoyama CB, Esser V, McGarry JD, Babior BM, Gottlieb RA (2000) Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine FEBS Lett 478:19–25

    Google Scholar 

  24. Di Marzio L, Alesse E, Ronciaoli P, Muzi P, Moretti S, Marcellini S, Amicosante G, De Simone C, Cifone MG (1997) Influence of L-carnitine on CD95 cross-lining-induced apoptosis and ceramide generation in human cell lines: correlation with its effects on purified acidic and neutral sphingomyelinases in vitro. Proc Assoc Am Physicians 109:154–163

    PubMed  Google Scholar 

  25. Haefen C von, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B, Daniel PT (2002) Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21:4009–4019

    Article  PubMed  Google Scholar 

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Acknowledgements

This research was supported in part by the Herzfelder Stiftung, Jubiläumsfonds der Österreichischen Nationalbank, and Bürgermeisterfonds der Stadt Wien.

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Authors and Affiliations

  1. Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, H. Collinstrasse 30, 1140, Vienna, Austria

    Heidrun Karlic, Claudia Laschan, Marlies Huemer, Elisabeth Guthann & Michael Pfeilstöcker

  2. Department of Medical Chemistry, University of Vienna, Vienna, Austria

    Alfred Lohninger & Marlies Huemer

  3. 3rd Medical Department, Hanusch Hospital, Vienna, Austria

    Claudia Laschan & Michael Pfeilstöcker

  4. Sozialmedizinisches Zentrum Sophienspital, Vienna, Austria

    Alexander Lapin & Franz Böhmer

  5. Ludwig Boltzmann Institute for Osteology, Vienna, Austria

    Marlies Huemer

  6. Otto Wagner Hospital, Vienna, Austria

    Eduard Rappold

Authors
  1. Heidrun Karlic
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  2. Alfred Lohninger
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  3. Claudia Laschan
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  9. Michael Pfeilstöcker
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Correspondence to Heidrun Karlic.

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Karlic, H., Lohninger, A., Laschan, C. et al. Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes. J Mol Med 81, 435–442 (2003). https://doi.org/10.1007/s00109-003-0447-6

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  • DOI: https://doi.org/10.1007/s00109-003-0447-6

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