Prevention of oxidant-induced cell death by lysosomotropic iron chelators

Hans L. Persson*, Zhengquan Yu, Oren Tirosh, John W. Eaton, Ulf T. Brunk

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

Abstract

Intralysosomal iron powerfully synergizes oxidant-induced cellular damage. The iron chelator, desferrioxamine (DFO), protects cultured cells against oxidant challenge but pharmacologically effective concentrations of this drug cannot readily be achieved in vivo. DFO localizes almost exclusively within the lysosomes following endocytic uptake, suggesting that truly lysosomotropic chelators might be even more effective. We hypothesized that an amine derivative of α-lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-ethyl)-amide (α-lipoic acid-plus [LAP]; pKa = 8.0), would concentrate via proton trapping within lysosomes, and that the vicinal thiols of the reduced form of this agent would interact with intralysosomal iron, preventing oxidant-mediated cell damage. Using a thiol-reactive fluorochrome, we find that reduced LAP does accumulate within the lysosomes of cultured J774 cells. Furthermore, LAP is approximately 1,000 and 5,000 times more effective than LM and DFO, respectively, in protecting lysosomes against oxidant-induced rupture and in preventing ensuing apoptotic cell death. Suppression of lysosomal accumulation of LAP (by ammonium-mediated lysosomal alkalinization) blocks these protective effects. Electron paramagnetic resonance reveals that the intracellular generation of hydroxyl radical following addition of hydrogen peroxide to J774 cells is totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2 μM) whereas LM (200 μM) is much less effective.

Original languageAmerican English
Pages (from-to)1295-1305
Number of pages11
JournalFree Radical Biology and Medicine
Volume34
Issue number10
DOIs
StatePublished - 15 May 2003

Bibliographical note

Funding Information:
We thank Dr. Robert Bjorklund for skillful technical assistance. Supported by the ÖLL Research Foundation, the Lions Foundation and the Research Funds of the Linköping University Hospital, Sweden (grants to H.L.P.), Swedish Medical Research Council and the Swedish Cancer Foundation (grants 4481 and 4296 to U.T.B.). J.W.E. was the recipient of a Visiting Professorship from the Linköping University Hospital, and of support from the National Institutes of Health (DK58882) and the Commonwealth of Kentucky Research Challenge Trust Fund.

Keywords

  • Free radicals
  • Iron
  • Iron-chelators
  • Lipoamide
  • Lipoic acid
  • Lysosomes
  • Macrophages
  • Oxidative stress

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