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A2E Inhibits Mitochondrial Function, Causes the Release of Pro-Apoptotic Proteins and Induces Apoptosis in Mammalian Cells

  • Christian Grimm
  • Marianne Suter
  • Andreas Wenzel
  • Marja Jäättela
  • Peter Esser
  • Norbert Kociok
  • Marcel Leist
  • Christoph Richter
  • Charlotte E. Remé

Summary

Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in humans living in industrialized countries. A precondition for AMD appears to be the accumulation of the age pigment lipofuscin in lysosomes of retinal pigment epithelial (RPE) cells. Here we show that A2E (N-retinyl-N-retinylidene ethanolamine) the major fluorophore of lipofuscin, induces apoptosis in RPE and other cells at concentrations found in human retina. Apoptosis is accompanied by appearance of the pro-apoptotic proteins cytochrome c and apoptosis inducing factor (AIF) in the cytoplasm and the nucleus but does not involve activation of caspase-3. Biochemical examinations show that A2E inhibits mitochondrial function by specifically targeting cytochrome oxidase (COX). With both, isolated mitochondria and purified COX, A2E inhibits oxygen consumption synergistically with light. Inhibition is reversed by addition of cytochrome c or cardiolipin. Loss of RPE cell viability through inhibition of mitochondrial function might constitute a pivotal step towards the progressive degeneration of the central retina. We present a working hypothesis that suggests that A2E, once released from lysosomes (by lysosomal rupture or by ‘overflow’ of the lysosomal capacity) can target mitochondria and inhibit mitochondrial function. This causes the release of the pro-apoptotic proteins and the induction of cell death.

Keywords

Retinal Pigment Epithelium Retinal Pigment Epithelium Cell Apoptosis Induce Factor Human Retinal Pigment Epithelial Cell Human Retinal Pigment Epithelium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Christian Grimm
    • 1
  • Marianne Suter
    • 2
  • Andreas Wenzel
    • 1
  • Marja Jäättela
    • 3
  • Peter Esser
    • 4
  • Norbert Kociok
    • 4
  • Marcel Leist
    • 5
  • Christoph Richter
    • 2
  • Charlotte E. Remé
    • 1
  1. 1.Department of OphthalmologyUniversity Hospital ZurichZurichSwitzerland
  2. 2.Institute of Biochemistry, Swiss Federal Institute of Technology (ETH)ZurichSwitzerland
  3. 3.Danish Cancer SocietyApoptosis LaboratoryCopenhagenDenmark
  4. 4.Eye ClinicUniversity of CologneCologneGermany
  5. 5.Department of Neurobiology, H. Lundbeck A/SValbyDenmark

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