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Docosahexaenoic Acid Enhances Iron Uptake by Modulating Iron Transporters and Accelerates Apoptotic Death in PC12 Cells

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Abstract

The effect of docosahexaenoic acid (DHA; 22:6 n–3) on Fe2+-mediated and/or H2O2-mediated oxidative stress (OS) was investigated in a PC12 pheochromocytoma cell line in the presence or absence of 50 ng/ml nerve growth factor (NGF). DHA-supplemented cells showed enhanced Fe2+-induced cell damage as evident by increased lipid peroxides formation (10-fold) and reduced neutral red (NR) dye uptake in a NGF-independent fashion. DHA caused a nearly 10-fold increase in free iron uptake in NGF-treated cells and doubled iron uptake in nondifferentiated cells. DHA-enrichment induced an elevation in the transferrin receptor protein in the nondifferentiated cells whereas NGF-treatment led to a substantial increase in the ubiquitous divalent metal ion transporter 1 (DMT-1) as detected by mRNA levels using qRT-PCR. The mechanism of action of DHA to accelerate cell death may be associated with the externalization of amino-phosphoglycerides (PG) species of which, increased ethanolamine plasmalogen levels, may be essential for cell rescue as noted in NGF-treated PC12 cells.

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Abbreviations

AA:

Arachidonic acid

DAPI:

4′,6-Diamidino-2-phenylindole

DHA:

Docosahexaenoic acid

DMT-1:

Divalent metal ion transporter 1

EPG:

Ethanolamine phosphoglyceride

FA:

Fatty acid

HIP:

Hexane/isopropanol

IRE:

Iron responsive element

LPO:

Lipid peroxidation

NGF:

Nerve growth factor

NPBI:

Nonprotein-bound iron

OS:

Oxidative stress

PG:

Phosphoglycerides

PUFA:

Polyunsaturated fatty acid

ROS:

Reactive oxygen species

TBARS:

Thiobarbituric acid reactive substances

TfR:

Transferrin receptor

TNBS:

2,4,6-Trinitrobenzenesulfonic acid

TNP:

Trinitrophenylate

TUNEL:

Terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling

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Acknowledgments

This work was supported by a grant provided by the Gulton Foundation (New York). We thank Moussa Youdim for enlightening our thoughts on the importance of iron in brain physiology and pathology.

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Authors and Affiliations

  1. Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Eldi Schonfeld, Ilanit Yasharel, Ephraim Yavin & Annette Brand

  2. The School of Nutritional Sciences, The Faculty of Agricultural Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot, 76100, Israel

    Annette Brand

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  1. Eldi Schonfeld
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  2. Ilanit Yasharel
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Correspondence to Annette Brand.

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Special issue dedicated to Dr. Moussa Youdim.

Equal scientific input of ES and AB.

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Schonfeld, E., Yasharel, I., Yavin, E. et al. Docosahexaenoic Acid Enhances Iron Uptake by Modulating Iron Transporters and Accelerates Apoptotic Death in PC12 Cells. Neurochem Res 32, 1673–1684 (2007). https://doi.org/10.1007/s11064-007-9378-x

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