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Involvement of mtDNA damage in free fatty acid-induced apoptosis

Valentina Grishko1, Lyudmila Rachek, Sergiy Musiyenko

  • 1Department of Cell Biology and Neuroscience, University of South Alabama College of Medicine, Mobile, AL 36688, USA.

Free Radical Biology & Medicine
|February 22, 2005
PubMed

Insights

Free fatty acids (FFA) damage mitochondrial DNA (mtDNA) in beta-cells, leading to apoptosis. Inhibiting inducible nitric oxide synthase (iNOS) protects against this FFA-induced damage and cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Endocrinology

Background:

  • Free fatty acids (FFA) are implicated in beta-cell dysfunction and death observed in diabetes.
  • Excessive nitric oxide (NO) generation via inducible nitric oxide synthase (iNOS) activation by FFA is a proposed mechanism.
  • The specific cellular targets of NO-induced damage in this context remain largely unidentified.

Purpose of the Study:

  • To investigate whether mitochondrial DNA (mtDNA) is a target of free fatty acid (FFA)-induced damage in beta-cells.
  • To elucidate the role of nitric oxide (NO) in FFA-mediated beta-cell toxicity.

Main Methods:

  • INS-1 cells were exposed to varying concentrations of FFA (oleate/palmitate).
  • Mitochondrial DNA (mtDNA) damage was assessed using ligation-mediated PCR.
  • Apoptosis was detected via DAPI staining and cytochrome c release.
  • The effect of the iNOS inhibitor aminoguanidine was evaluated.

Main Results:

  • FFA exposure led to a dose-dependent increase in mtDNA damage.
  • The DNA damage pattern was consistent with NO-induced damage.
  • FFA treatment induced apoptosis, evidenced by DAPI staining and cytochrome c release.
  • Aminoguanidine treatment protected INS-1 cells from FFA-induced mtDNA damage and apoptosis.

Conclusions:

  • Mitochondrial DNA (mtDNA) is a sensitive target for nitric oxide (NO)-induced toxicity in beta-cells.
  • FFA-induced beta-cell apoptosis may be mediated by NO-induced mtDNA damage.
  • Inhibition of inducible nitric oxide synthase (iNOS) offers a potential protective strategy against FFA-induced beta-cell damage.

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