AIF depletion provides neuroprotection through a preconditioning effect

Eva-Maria Öxler, Amalia Dolga, C Culmsee

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

Previous studies established a major role for apoptosis inducing factor (AIF) in neuronal cell death after acute brain injury. For example, AIF translocation from mitochondria to the nucleus determined delayed neuronal death, whereas reduced AIF expression provided neuroprotective effects in models of cerebral ischemia or brain trauma. The question remains, however, why reduced AIF levels are sufficient to mediate neuroprotection, since only very little AIF translocation to the nucleus is required for induction of cell death. Thus, the present study addresses the question, whether AIF gene silencing affects intrinsic death pathways upstream of nuclear translocation at the level of the mitochondria. Using MTT assays and real-time cell impedance measurements we confirmed the protective effect of AIF siRNA against glutamate toxicity in immortalized mouse hippocampal HT-22 neurons. Further, AIF siRNA prevented glutamate-induced mitochondrial fragmentation and loss of mitochondrial membrane potential. The protection of mitochondrial integrity was associated with preserved ATP levels, attenuated increases in lipid peroxidation and reduced complex I expression levels. Notably, low concentrations of the complex I inhibitor rotenone (20 nM), provided similar protective effects against glutamate toxicity at the mitochondrial level. These results expose a preconditioning effect as a mechanism for neuroprotection mediated by AIF depletion. In particular, they point out an association between mitochondrial complex I and AIF, which regulate each other's stability in mitochondria. Overall, these findings postulate that AIF depletion mediates a preconditioning effect protecting neuronal cells from subsequent glutamate toxicity through reduced levels of complex I protein.

Original languageEnglish
Pages (from-to)1027-38
Number of pages12
JournalApoptosis
Volume17
Issue number10
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Animals
  • Apoptosis
  • Apoptosis Inducing Factor
  • Cell Death
  • Cell Nucleus
  • Cells, Cultured
  • Down-Regulation
  • Electron Transport Complex I
  • Gene Silencing
  • Glutamic Acid
  • Hippocampus
  • Mice
  • Mitochondria
  • Neurons
  • RNA, Small Interfering
  • Rotenone

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