Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria

Hanyu Liang, Qitao Ran, Youngmok Charles Jang, Deborah Holstein, James Lechleiter, Tiffany McDonald-Marsh, Andrej Musatov, Wook Song, Holly Van Remmen, Arlan Richardson

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Glutathione peroxidase 4 (Gpx4) is a unique antioxidant enzyme that repairs oxidative damage to biomembranes. In this study, we examined the effects of Gpx4 on the release of various apoptogenic proteins from mitochondria using transgenic mice overexpressing Gpx4 [Tg(GPX4+/0)] and mice deficient in Gpx4 (Gpx4+/- mice). Diquat exposure triggered apoptosis that occurred through an intrinsic pathway and resulted in the mitochondrial release of cytochrome c (Cyt c), Smac/DIABLO, and Omi/HtrA2 in the liver of wild-type (Wt) mice. Liver apoptosis and Cyt c release were suppressed in Tg(GPX4+/0) mice but exacerbated in Gpx4+/- mice; however, neither the Tg(GPX4+/0) nor the Gpx4+/- mice showed any alterations in the levels of Smac/DIABLO or Omi/HtrA2 released from mitochondria. Submitochondrial fractionation data showed that Smac/DIABLO and Omi/HtrA2 existed primarily in the intermembrane space and matrix, whereas Cyt c and Gpx4 were both associated with the inner membrane. In addition, diquat exposure induced cardiolipin peroxidation in the liver of Wt mice; the levels of cardiolipin peroxidation were reduced in Tg(GPX4+/0) mice but elevated in Gpx4+/- mice. These data suggest that Gpx4 differentially regulates apoptogenic protein release owing to its inner membrane location in mitochondria and its ability to repair cardiolipin peroxidation.

Original languageEnglish (US)
Pages (from-to)312-320
Number of pages9
JournalFree Radical Biology and Medicine
Volume47
Issue number3
DOIs
StatePublished - Aug 1 2009

Keywords

  • Apoptosis
  • Cardiolipin
  • Free radicals
  • Gpx4
  • Lipid peroxidation
  • Oxidative stress
  • Phospholipid hydroperoxide glutathione peroxidase 4

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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