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Aberrant regulation of choline metabolism by mitochondrial electron transport system inhibition in neuroblastoma cells

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Abstract

Anomalous choline metabolic patterns have been consistently observed in vivo using Magnetic Resonance Spectroscopy (MRS) analysis of patients with neurodegenerative diseases and tissues from cancer patient. It remains unclear; however, what signaling events may have triggered these choline metabolic aberrancies. This study investigates how changes in choline and phospholipid metabolism are regulated by distinct changes in the mitochondrial electron transport system (ETS). We used specific inhibitors to down regulate the function of individual protein complexes in the ETS of SH-SY5Y neuroblastoma cells. Interestingly, we found that dramatic elevation in the levels of phosphatidylcholine metabolites could be induced by the inhibition of individual ETS complexes, similar to in vivo observations. Such interferences produced divergent metabolic patterns, which were distinguishable via principal component analysis of the cellular metabolomes. Functional impairments in ETS components have been reported in several central nervous system (CNS) diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD); however, it remains largely unknown how the suppression of individual ETS complex function could lead to specific dysfunction in different cell types, resulting in distinct disease phenotypes. Our results suggest that the inhibition of each of the five ETS complexes might differentially regulate phospholipase activities within choline metabolic pathways in neuronal cells, which could contribute to the overall understanding of mitochondrial diseases.

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Abbreviations

AA:

Arachidonic acid

AD:

Alzheimer’s disease

ANOVA:

Analysis of variance

CDP-Cho:

Cytidine diphosphate choline

Cho:

Choline

CNS:

Central nervous system

ETS:

Electron transport system

GPC:

Glycerophosphorylcholine

GPC-PDE:

Glycerophosphorylcholine phosphodiesterase

HD:

Huntington’s disease

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

HIF-1α:

Hypoxia-inducible factor-1α

Htt:

Huntington gene

MALDI-TOF:

Matrix-assisted laser desorption/ionization

MS:

Mass spectrometry

NAA:

Non-essential amino acids

NMR:

Nuclear magnetic resonance spectroscopy

3-NP:

3-Nitropropionic acid

PCA:

Principal component analysis

PC:

Phosphorylcholine

PD:

Parkinson’s disease

PLA2 :

Phospholipase A2

PLC:

Phospholipase C

PLD:

Phospholipase D

PtdCho:

Phosphatidylcholine

ROS:

Reactive oxygen species

Tau:

Taurine

tCho:

Total choline

TSP:

3-(trimethylsilyl)propionic-2,2,3,3-d4 acid

References

  • Aboagye, E. O., & Bhujwalla, Z. M. (1999). Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Research, 59, 80–84.

    PubMed  CAS  Google Scholar 

  • Barker, P. B., Glickson, J. D., & Bryan, R. N. (1993). In vivo magnetic resonance spectroscopy of human brain tumors. Topics in Magnetic Resonance Imaging, 5, 32–45. doi:10.1097/00002142-199300520-00006.

    Article  PubMed  CAS  Google Scholar 

  • Beal, M. F. (1998). Mitochondrial dysfunction in neurodegenerative diseases. Biochimica et Biophysica Acta, 1366, 211–223. doi:10.1016/S0005-2728(98)00114-5.

    Article  PubMed  CAS  Google Scholar 

  • Beal, M. F., Brouillet, E., Jenkins, B. G., Ferrante, R. J., Kowall, N. W., Miller, J. M., et al. (1993). Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. The Journal of Neuroscience, 13, 4181–4192.

    PubMed  CAS  Google Scholar 

  • Bove, J., Prou, D., Perier, C., & Przedborski, S. (2005). Toxin-induced models of Parkinson’s disease. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, 2, 484–494.

    Google Scholar 

  • Brouillet, E., Conde, F., Beal, M. F., & Hantraye, P. (1999). Replicating Huntington’s disease phenotype in experimental animals. Progress in Neurobiology, 59, 427–468. doi:10.1016/S0301-0082(99)00005-2.

    Article  PubMed  CAS  Google Scholar 

  • Browne, S. E., Bowling, A. C., MacGarvey, U., Baik, M. J., Berger, S. C., Muqit, M. M., et al. (1997). Oxidative damage and metabolic dysfunction in Huntington’s disease: Selective vulnerability of the basal ganglia. Annals of Neurology, 41, 646–653. doi:10.1002/ana.410410514.

    Article  PubMed  CAS  Google Scholar 

  • Choi, S. Y., Huang, P., Jenkins, G. M., Chan, D. C., Schiller, J., & Frohman, M. A. (2006). A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nature Cell Biology, 8, 1255–1262. doi:10.1038/ncb1487.

    Article  PubMed  CAS  Google Scholar 

  • Clarke, C. E., & Lowry, M. (2000). Basal ganglia metabolite concentrations in idiopathic Parkinson’s disease and multiple system atrophy measured by proton magnetic resonance spectroscopy. European Journal of Neurology, 7, 661–665. doi:10.1046/j.1468-1331.2000.00111.x.

    Article  PubMed  CAS  Google Scholar 

  • Farber, S. A., Slack, B. E., & Blusztajn, J. K. (2000). Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: A model of the membrane defect of Alzheimer’s disease. The FASEB Journal, 14, 2198–2206. doi:10.1096/fj.99-0853.

    Article  PubMed  CAS  Google Scholar 

  • Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2000). Glycerophospholipids in brain: Their metabolism, incorporation into membranes, functions, and involvement in neurological disorders. Chemistry and Physics of Lipids, 106, 1–29. doi:10.1016/S0009-3084(00)00128-6.

    Article  PubMed  CAS  Google Scholar 

  • Glunde, K., Jacobs, M. A., & Bhujwalla, Z. M. (2006). Choline metabolism in cancer: Implications for diagnosis and therapy. Expert Review of Molecular Diagnostics, 6, 821–829. doi:10.1586/14737159.6.6.821.

    Article  PubMed  CAS  Google Scholar 

  • Glunde, K., Shah, T., Winnard, P. T., Jr., Raman, V., Takagi, T., Vesuna, F., et al. (2008). Hypoxia regulates choline kinase expression through hypoxia-inducible factor-1 alpha signaling in a human prostate cancer model. Cancer Research, 68, 172–180. doi:10.1158/0008-5472.CAN-07-2678.

    Article  PubMed  CAS  Google Scholar 

  • Govindaraju, V., Young, K., & Maudsley, A. A. (2000). Proton NMR chemical shifts and coupling constants for brain metabolites. NMR in Biomedicine, 13, 129–153. doi :10.1002/1099-1492(200005)13:3<129::AID-NBM619>3.0.CO;2-V.

    Article  PubMed  CAS  Google Scholar 

  • Jenkins, B. G., Choi, J.-K., & Beal, M. F. (2005). Magnetic resonance spectroscopy of neurodegenerative illness. In M. F. Beal, A. E. Lang & A. Ludolph (Eds.), Neurodegenerative Diseases. London: Cambridge University Press.

    Google Scholar 

  • Jenkins, B. G., Koroshetz, W. J., Beal, M. F., & Rosen, B. R. (1993). Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology, 43, 2689–2695.

    PubMed  CAS  Google Scholar 

  • Kanthasamy, A. G., Borowitz, J. L., Pavlakovic, G., & Isom, G. E. (1994). Dopaminergic neurotoxicity of cyanide: Neurochemical, histological, and behavioral characterization. Toxicology and Applied Pharmacology, 126, 156–163. doi:10.1006/taap.1994.1102.

    Article  PubMed  CAS  Google Scholar 

  • Kinsey, G. R., McHowat, J., Beckett, C. S., & Schnellmann, R. G. (2007). Identification of calcium-independent phospholipase A2gamma in mitochondria and its role in mitochondrial oxidative stress. American Journal of Physiology. Renal Physiology, 292, F853–F860. doi:10.1152/ajprenal.00318.2006.

    Article  PubMed  CAS  Google Scholar 

  • Li, Z., & Vance, D. E. (2008). Phosphatidylcholine and choline homeostasis. Jornal of Lipid Research, 48, 1187–1194.

    Article  CAS  Google Scholar 

  • MacKay, S., Ezekiel, F., Di Sclafani, V., Meyerhoff, D. J., Gerson, J., Norman, D., et al. (1996). Alzheimer disease and subcortical ischemic vascular dementia: Evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology, 198, 537–545.

    PubMed  CAS  Google Scholar 

  • Meyerhoff, D. J., MacKay, S., Constans, J. M., Norman, D., Van Dyke, C., Fein, G., et al. (1994). Axonal injury and membrane alterations in Alzheimer’s disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Annals of Neurology, 36, 40–47. doi:10.1002/ana.410360110.

    Article  PubMed  CAS  Google Scholar 

  • Michel, V., Yuan, Z., Ramsubir, S., & Bakovic, M. (2006). Choline transport for phospholipid synthesis. Experimental Biology and Medicine (Maywood, NJ), 231, 490–504.

    CAS  Google Scholar 

  • Negendank, W. (1992). Studies of human tumors by MRS: A review. NMR in Biomedicine, 5, 303–324.

    PubMed  CAS  Google Scholar 

  • Ohta, S., & Ohsawa, I. (2006). Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer’s disease: On defects in the cytochrome c oxidase complex and aldehyde detoxification. Journal of Alzheimer’s Disease, 9, 155–166.

    PubMed  Google Scholar 

  • Oude Weernink, P. A., López de Jesús, M., & Schmidt, M. (2007). Phospholipase D signaling: Orchestration by PIP2 and small GTPases. Naunyn-Schmiedeberg’s Archives of Pharmacology, 374, 399–411. doi:10.1007/s00210-007-0131-4.

    Article  PubMed  CAS  Google Scholar 

  • Pears, M. R., Cooper, J. D., Mitchison, H. M., Mortishire-Smith, R. J., Pearce, D. A., & Griffin, J. L. (2005). High resolution 1H NMR-based metabolomics indicates a neurotransmitter cycling deficit in cerebral tissue from a mouse model of Batten disease. The Journal of Biological Chemistry, 280, 42508–42514. doi:10.1074/jbc.M507380200.

    Article  PubMed  CAS  Google Scholar 

  • Podo, F. (1999). Tumour phospholipid metabolism. NMR in Biomedicine, 12, 413–439. doi :10.1002/(SICI)1099-1492(199911)12:7<413::AID-NBM587>3.0.CO;2-U.

    Article  PubMed  CAS  Google Scholar 

  • Schapira, A. H., Cooper, J. M., Dexter, D., Jenner, P., Clark, J. B., & Marsden, C. D. (1989). Mitochondrial complex I deficiency in Parkinson’s disease. Lancet, 1, 1269. doi:10.1016/S0140-6736(89)92366-0.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, N., & Ferger, B. (2001). Neurochemical findings in the MPTP model of Parkinson’s disease. Journal of Neural Transmission, 108, 1263–1282. doi:10.1007/s007020100004.

    Article  PubMed  CAS  Google Scholar 

  • Sharpley, M. S., Shannon, R. J., Draghi, F., & Hirst, J. (2006). Interactions between phospholipids and NADH:ubiquinone oxidoreductase (complex I) from bovine mitochondria. Biochemistry, 45, 241–248. doi:10.1021/bi051809x.

    Article  PubMed  CAS  Google Scholar 

  • Sherer, T. B., Betarbet, R., Stout, A. K., Lund, S., Baptista, M., Panov, A. V., et al. (2002). An in vitro model of Parkinson’s disease: Linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. The Journal of Neuroscience, 22, 7006–7015.

    PubMed  CAS  Google Scholar 

  • Steinhour, E., Sherwani, S. I., Mazerik, J. N., Ciapala, V., O’Connor Butler, E., Cruff, J. P., et al. (2008) Redox-active antioxidant modulation of lipid signaling in vascular endothelial cells: Vitamin C induces activation of phospholipase D through phospholipase A(2), lipoxygenase, and cyclooxygenase. Molecular and Cellular Biochemistry, 315, 97–112.

    Article  PubMed  CAS  Google Scholar 

  • Tetrud, J. W., & Langston, J. W. (1989). MPTP-induced parkinsonism as a model for Parkinson’s disease. Acta Neurologica Scandinavica. Supplementum, 126, 35–40.

    Article  PubMed  CAS  Google Scholar 

  • van Meer, G., Voelker, D. R., & Feigenson, G. W. (2008). Membrane lipids: Where they are and how they behave. Nature Reviews. Molecular Cell Biology, 9, 112–124. doi:10.1038/nrm2330.

    Article  PubMed  CAS  Google Scholar 

  • Wolf, R. A., & Gross, R. W. (1985). Identification of neutral active phospholipase C which hydrolyzes choline glycerophospholipids and plasmalogen selective phospholipase A2 in canine myocardium. The Journal of Biological Chemistry, 260, 7295–7303.

    PubMed  CAS  Google Scholar 

  • Zeisel, S. H., & Blusztajn, J. K. (1994). Choline and human nutrition. Annual Review of Nutrition, 14, 269–296. doi:10.1146/annurev.nu.14.070194.001413.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, D., Lai, Y., Shelat, P. B., Hu, C., Sun, G. Y., & Lee, J. C. (2006). Phospholipases A2 mediate amyloid-beta peptide-induced mitochondrial dysfunction. The Journal of Neuroscience, 26, 11111–11119. doi:10.1523/JNEUROSCI.3505-06.2006.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work is supported in part by an NIH grant NS046593 and the Foundation of UMDNJ.

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Authors and Affiliations

  1. Center for Advanced Proteomics Research and Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School Cancer Center, Newark, NJ, 07103, USA

    Ahmet T. Baykal, Mohit R. Jain & Hong Li

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  1. Ahmet T. Baykal
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  2. Mohit R. Jain
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  3. Hong Li
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Correspondence to Hong Li.

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Baykal, A.T., Jain, M.R. & Li, H. Aberrant regulation of choline metabolism by mitochondrial electron transport system inhibition in neuroblastoma cells. Metabolomics 4, 347–356 (2008). https://doi.org/10.1007/s11306-008-0125-3

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