Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria.
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.
Liang
Hanyu
H
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Ran
Qitao
Q
Jang
Youngmok Charles
YC
Holstein
Deborah
D
Lechleiter
James
J
McDonald-Marsh
Tiffany
T
Musatov
Andrej
A
Song
Wook
W
Van Remmen
Holly
H
Richardson
Arlan
A
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D004178:Diquat / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D015227:Lipid Peroxidation; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D021381:Protein Transport / Q000502:physiology; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002308:Cardiolipins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D004178:Diquat; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse