Mitochondrial glutathione peroxidase 4 is indispensable for photoreceptor development and survival in mice

Abstract

Glutathione peroxidase 4 (GPx4) is known for its unique function in the direct detoxification of lipid peroxides in the cell membrane and as a key regulator of ferroptosis, a form of lipid peroxidation–induced nonapoptotic cell death. However, the cytosolic isoform of GPx4 is considered to play a major role in inhibiting ferroptosis in somatic cells, whereas the roles of the mitochondrial isoform of GPx4 (mGPx4) in cell survival are not yet clear. In the present study, we found that mGPx4 KO mice exhibit a cone–rod dystrophy-like phenotype in which loss of cone photoreceptors precedes loss of rod photoreceptors. Specifically, in mGPx4 KO mice, cone photoreceptors disappeared prior to their maturation, whereas rod photoreceptors persisted through maturation but gradually degenerated afterward. Mechanistically, we demonstrated that vitamin E supplementation significantly ameliorated photoreceptor loss in these mice. Furthermore, LC–MS showed a significant increase in peroxidized phosphatidylethanolamine esterified with docosahexaenoic acid in the retina of mGPx4 KO mice. We also observed shrunken and uniformly condensed nuclei as well as caspase-3 activation in mGPx4 KO photoreceptors, suggesting that apoptosis was prevalent. Taken together, our findings indicate that mGPx4 is essential for the maturation of cone photoreceptors but not for the maturation of rod photoreceptors, although it is still critical for the survival of rod photoreceptors after maturation. In conclusion, we reveal novel functions of mGPx4 in supporting development and survival of photoreceptors in vivo. Glutathione peroxidase 4 (GPx4) is known for its unique function in the direct detoxification of lipid peroxides in the cell membrane and as a key regulator of ferroptosis, a form of lipid peroxidation–induced nonapoptotic cell death. However, the cytosolic isoform of GPx4 is considered to play a major role in inhibiting ferroptosis in somatic cells, whereas the roles of the mitochondrial isoform of GPx4 (mGPx4) in cell survival are not yet clear. In the present study, we found that mGPx4 KO mice exhibit a cone–rod dystrophy-like phenotype in which loss of cone photoreceptors precedes loss of rod photoreceptors. Specifically, in mGPx4 KO mice, cone photoreceptors disappeared prior to their maturation, whereas rod photoreceptors persisted through maturation but gradually degenerated afterward. Mechanistically, we demonstrated that vitamin E supplementation significantly ameliorated photoreceptor loss in these mice. Furthermore, LC–MS showed a significant increase in peroxidized phosphatidylethanolamine esterified with docosahexaenoic acid in the retina of mGPx4 KO mice. We also observed shrunken and uniformly condensed nuclei as well as caspase-3 activation in mGPx4 KO photoreceptors, suggesting that apoptosis was prevalent. Taken together, our findings indicate that mGPx4 is essential for the maturation of cone photoreceptors but not for the maturation of rod photoreceptors, although it is still critical for the survival of rod photoreceptors after maturation. In conclusion, we reveal novel functions of mGPx4 in supporting development and survival of photoreceptors in vivo. Glutathione peroxidase 4 (GPx4) is a ubiquitously expressed antioxidant enzyme with a unique function that directly reduces peroxidized phospholipids in the cell membrane. GPx4 is known as a critical regulator of ferroptosis (1Yang W.S. SriRamaratnam R. Welsch M.E. Shimada K. Skouta R. Viswanathan V.S. Cheah J.H. Clemons P.A. Shamji A.F. Clish C.B. Brown L.M. Girotti A.W. Cornish V.W. Schreiber S.L. Stockwell B.R. Regulation of ferroptotic cancer cell death by GPX4.Cell. 2014; 156: 317-331Abstract Full Text Full Text PDF PubMed Scopus (2181) Google Scholar), lipid peroxidation–induced nonapoptotic cell death, and indispensable for development and survival. A conventional KO of GPx4 in mice leads to early embryonic death (2Imai H. Hirao F. Sakamoto T. Sekine K. Mizukura Y. Saito M. Kitamoto T. Hayasaka M. Hanaoka K. Nakagawa Y. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene.Biochem. Biophys. Res. Commun. 2003; 305: 278-286Crossref PubMed Scopus (252) Google Scholar). Conditional KO of GPx4 in the heart and liver has been shown to cause embryonic and neonatal death, respectively (3Imai H. Matsuoka M. Kumagai T. Sakamoto T. Koumura T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis.in: Nagata S. Nakano H. Apoptotic and Non-apoptotic Cell Death. 403. Current Topics in Microbiology and Immunology, Springer International Publishing, Cham2016: 143-170Crossref Scopus (243) Google Scholar, 4Carlson B.A. Tobe R. Yefremova E. Tsuji P.A. Hoffmann V.J. Schweizer U. Gladyshev V.N. Hatfield D.L. Conrad M. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration.Redox Biol. 2016; 9: 22-31Crossref PubMed Scopus (130) Google Scholar), whereas loss of GPx4 specifically in spermatocytes causes male infertility (5Imai H. Hakkaku N. Iwamoto R. Suzuki J. Suzuki T. Tajima Y. Konishi K. Minami S. Ichinose S. Ishizaka K. Shioda S. Arata S. Nishimura M. Naito S. Nakagawa Y. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice.J. Biol. Chem. 2009; 284: 32522-32532Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Furthermore, tamoxifen-induced GPx4 KO is known to cause acute renal failure and death (6Friedmann Angeli J.P. Schneider M. Proneth B. Tyurina Y.Y. Tyurin V.A. Hammond V.J. Herbach N. Aichler M. Walch A. Eggenhofer E. Basavarajappa D. Rådmark O. Kobayashi S. Seibt T. Beck H. et al.Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.Nat. Cell Biol. 2014; 16: 1180-1191Crossref PubMed Scopus (1244) Google Scholar). GPx4 consists of three isoforms; mitochondrial (mGPx4), nucleolar (nGPx4), and cytosolic (cGPx4), which are located at the mitochondria, nucleolus, and the other subcellular spaces, respectively (7Arai M. Imai H. Sumi D. Imanaka T. Takano T. Chiba N. Nakagawa Y. Import into mitochondria of phospholipid hydroperoxide glutathione peroxidase requires a leader sequence.Biochem. Biophys. Res. Commun. 1996; 227: 433-439Crossref PubMed Scopus (94) Google Scholar, 8Nakamura T. Imai H. Tsunashima N. Nakagawa Y. Molecular cloning and functional expression of nucleolar phospholipid hydroperoxide glutathione peroxidase in mammalian cells.Biochem. Biophys. Res. Commun. 2003; 311: 139-148Crossref PubMed Scopus (21) Google Scholar). In somatic tissues and cultured cells, cGPx4 is considered dominantly expressed relative to mGPx4 and nGPx4 (9Imai H. Saito M. Kirai N. Hasegawa J. Konishi K. Hattori H. Nishimura M. Naito S. Nakagawa Y. Identification of the positive regulatory and distinct core regions of promoters, and transcriptional regulation in three types of mouse phospholipid hydroperoxide glutathione peroxidase.J. Biochem. (Tokyo). 2006; 140: 573-590Crossref PubMed Scopus (22) Google Scholar). In addition, cGPx4 KO mice die embryonically, whereas mGPx4 or nGPx4 KO does not affect development and survival, except for male infertility in mGPx4 KO mice (3Imai H. Matsuoka M. Kumagai T. Sakamoto T. Koumura T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis.in: Nagata S. Nakano H. Apoptotic and Non-apoptotic Cell Death. 403. Current Topics in Microbiology and Immunology, Springer International Publishing, Cham2016: 143-170Crossref Scopus (243) Google Scholar, 10Schneider M. Förster H. Boersma A. Seiler A. Wehnes H. Sinowatz F. Neumüller Walch A. M. F. A. M. M. et glutathione peroxidase 4 disruption causes male J. Biol. 2009; PubMed Scopus Google Scholar). In addition, the lethality caused by GPx4 KO by cGPx4 but not by mGPx4 or nGPx4 (3Imai H. Matsuoka M. Kumagai T. Sakamoto T. Koumura T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis.in: Nagata S. Nakano H. Apoptotic and Non-apoptotic Cell Death. 403. Current Topics in Microbiology and Immunology, Springer International Publishing, Cham2016: 143-170Crossref Scopus (243) Google Scholar, H. R. A. form glutathione peroxidase 4 is the essential isoform for survival and somatic mitochondrial Biol. Chem. 2009; 284: Full Text Full Text PDF PubMed Scopus Google Scholar, H. of functional of PHGPx mice and Biochem. PubMed Scopus Google Scholar). that cGPx4 is the key isoform for survival, whereas the role of mGPx4 is not yet of and play roles in the by with photoreceptors in and cone photoreceptors in and docosahexaenoic acid are at the of photoreceptors and are to and of in the Lipid Res. PubMed Scopus Google Scholar, J.P. role of in and of the Res. PubMed Scopus Google Scholar). In addition, photoreceptors are also known to the of and through in mitochondria located at the of photoreceptors of the PubMed Google Scholar). We that KO of GPx4 in photoreceptors in mice to early the of GPx4 for the survival of photoreceptors T. T. T. Y. Nakagawa Y. Imai H. Y. Glutathione peroxidase 4 is for maturation of photoreceptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the present study, to the roles of we the of mGPx4 KO mice. we found a phenotype of in which cone and rod photoreceptors but with and at our findings into roles of We GPx4 mice by with a (2Imai H. Hirao F. Sakamoto T. Sekine K. Mizukura Y. Saito M. Kitamoto T. Hayasaka M. Hanaoka K. Nakagawa Y. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene.Biochem. Biophys. Res. Commun. 2003; 305: 278-286Crossref PubMed Scopus (252) Google Scholar), and the embryonic lethality of GPx4 KO mice was by that of GPx4 (9Imai H. Saito M. Kirai N. Hasegawa J. Konishi K. Hattori H. Nishimura M. Naito S. Nakagawa Y. Identification of the positive regulatory and distinct core regions of promoters, and transcriptional regulation in three types of mouse phospholipid hydroperoxide glutathione peroxidase.J. Biochem. (Tokyo). 2006; 140: 573-590Crossref PubMed Scopus (22) Google Scholar, H. of functional of PHGPx mice and Biochem. PubMed Scopus Google Scholar, T. T. T. Y. Nakagawa Y. Imai H. Y. Glutathione peroxidase 4 is for maturation of photoreceptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). study, mGPx4 KO mice in which the lethality of GPx4 KO was by mGPx4 KO A and that cGPx4 and nGPx4 but of the that GPx4 expression was in the mitochondria, whereas in the and in mGPx4 KO mice In mice in which in mGPx4 KO mice are by a of GPx4 as mice. mGPx4 in the cytosolic and mitochondrial of the retina and in KO GPx4 was not in the mitochondrial whereas the of GPx4 in the to in and retina A and of mGPx4 KO retina showed that GPx4 expression is in the of photoreceptors mitochondria are condensed the mGPx4 KO mouse at with and with the mouse retina a of lipid was in the mGPx4 KO mouse retina at with in the mouse retina a after in photoreceptors that at the In rod photoreceptors at whereas cone photoreceptors with not observed as early as not that the the photoreceptors and is not to shown that a vitamin E cell death caused by GPx4 in and in (3Imai H. Matsuoka M. Kumagai T. Sakamoto T. Koumura T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis.in: Nagata S. Nakano H. Apoptotic and Non-apoptotic Cell Death. 403. Current Topics in Microbiology and Immunology, Springer International Publishing, Cham2016: 143-170Crossref Scopus (243) Google Scholar, 4Carlson B.A. Tobe R. Yefremova E. Tsuji P.A. Hoffmann V.J. Schweizer U. Gladyshev V.N. Hatfield D.L. Conrad M. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration.Redox Biol. 2016; 9: 22-31Crossref PubMed Scopus (130) Google Scholar, H. Hakkaku N. Iwamoto R. Suzuki J. Suzuki T. Tajima Y. Konishi K. Minami S. Ichinose S. Ishizaka K. Shioda S. Arata S. Nishimura M. Naito S. Nakagawa Y. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice.J. Biol. Chem. 2009; 284: 32522-32532Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, W.S. R. of the ferroptosis glutathione peroxidase 4 in in and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, W.S. Stockwell B.R. nonapoptotic cell death in cancer Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. J. Sakamoto T. H. K. Y. A. Saito N. T. N. Y. Kobayashi K. S. H. et of cell ferroptosis in Commun. PubMed Scopus Google Scholar, K. J. M. Sakamoto T. Koumura T. S. H. Y. A. Saito N. T. Y. Kobayashi K. S. Y. et of lipid in PubMed Scopus (22) Google Scholar), through its of lipid Y. E lipid and in with Res. PubMed Scopus Google Scholar). the of E in to mice a to the of the through which the also with E. We found that the of mGPx4 KO mice was significantly the of mice a A and of in the significantly in mGPx4 KO mice a and was significantly by E supplementation A and we the of mGPx4 KO and E supplementation in cone photoreceptors that expression of a of cone photoreceptors, was not observed in mGPx4 KO mice, and the by E supplementation was although significant and the expression of cone of cone photoreceptors, was not observed in the mGPx4 KO and E supplementation not a significant In the expression of a of cone photoreceptor was expressed at in the retina of mGPx4 KO mice, although it disappeared by E supplementation the loss of cone and significantly the of photoreceptors at and indicate that peroxidized phospholipids in mitochondria are essential for the development of cone photoreceptors. However, rod photoreceptors to their although mGPx4 KO causes rod photoreceptor death at a the in the of mGPx4 cone and rod photoreceptors, of and of the was significantly in mGPx4 KO mice at with the mice In mGPx4 KO mice, the of and was significantly that in mGPx4 KO mice E In the in mice, the of and was significantly in mGPx4 KO mice that in mice. E supplementation not and which was with our in indicate that E in rod photoreceptors but not in cone photoreceptors. In addition, with our findings and mGPx4 KO mice of the key for cone–rod the roles of the retina at was of the mitochondria in the of mGPx4 KO mouse photoreceptors that the of mitochondria was significantly and that the was significantly relative to in mice the of mitochondrial of mitochondrial caused by mGPx4 to mitochondrial by of the mitochondrial significantly in the mGPx4 KO mouse retina with in the mouse retina of the mitochondria mitochondrial in mGPx4 KO photoreceptors, whereas it was not observed in mice In was significant in the of other as of at and In a study, it was that mitochondria in photoreceptor with of M. M.E. T. of membrane photoreceptor regulated by U. S. A. PubMed Scopus Google Scholar). mitochondrial was in our mice, whereas it in mGPx4 KO mice the photoreceptor death was caused by mGPx4 the subcellular of photoreceptors was uniformly and nuclei observed in the of mGPx4 KO mice, but not in that of the A and cell death S. A of cell PubMed Scopus Google Scholar). by the of caspase-3 activation in the photoreceptors of mGPx4 KO mice that was by E phospholipids are for functions and survival. the of mGPx4 LC–MS was to phosphatidylethanolamine and the major phospholipids in mitochondria role of phospholipids in mitochondrial and PubMed Scopus Google Scholar), the the mGPx4 and mGPx4 KO mice at that the early of photoreceptor of of to in mGPx4 KO in the and mGPx4 KO Specifically, the relative of which of was significantly in mGPx4 KO in and mGPx4 KO peroxidized was significantly in mGPx4 KO mouse with the in and mGPx4 KO mouse also to in mGPx4 KO but was not was significant in the form of peroxidized the three was a for of to and to increase although not at significant shown in a M. Förster H. Boersma A. Seiler A. Wehnes H. Sinowatz F. Neumüller Walch A. M. F. A. M. M. et glutathione peroxidase 4 disruption causes male J. Biol. 2009; PubMed Scopus Google Scholar), our mGPx4 KO mice also with male infertility and in the of the in mGPx4 KO mice of mGPx4 KO into and mitochondrial membrane of mGPx4 KO was significantly E the mitochondrial membrane but was not to the or male suggesting a role of mGPx4 in the was observed in the of mGPx4 KO mice and was in the of mGPx4 KO and mice In our that KO of of GPx4 in mice a loss in the of and in the (5Imai H. Hakkaku N. Iwamoto R. Suzuki J. Suzuki T. Tajima Y. Konishi K. Minami S. Ichinose S. Ishizaka K. Shioda S. Arata S. Nishimura M. Naito S. Nakagawa Y. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice.J. Biol. Chem. 2009; 284: 32522-32532Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), suggesting that mGPx4 is for the of for the survival of GPx4 is for the development and survival of types of However, the roles of GPx4 are still and by other shown that mGPx4 KO mice but exhibit male infertility of and M. Förster H. Boersma A. Seiler A. Wehnes H. Sinowatz F. Neumüller Walch A. M. F. A. M. M. et glutathione peroxidase 4 disruption causes male J. Biol. 2009; PubMed Scopus Google Scholar, H. R. A. form glutathione peroxidase 4 is the essential isoform for survival and somatic mitochondrial Biol. Chem. 2009; 284: Full Text Full Text PDF PubMed Scopus Google Scholar). in the somatic cGPx4 has been to dominantly expressed and mGPx4 in the has been considered to M. Förster H. Boersma A. Seiler A. Wehnes H. Sinowatz F. Neumüller Walch A. M. F. A. M. M. et glutathione peroxidase 4 disruption causes male J. Biol. 2009; PubMed Scopus Google Scholar). that mGPx4 is in photoreceptors. We that the loss of of GPx4 in photoreceptors to cell death T. T. T. Y. Nakagawa Y. Imai H. Y. Glutathione peroxidase 4 is for maturation of photoreceptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the roles of GPx4 in photoreceptors not present the role of mGPx4 in photoreceptor survival in vivo. In to other somatic in which cGPx4 is mGPx4 M. Förster H. Boersma A. Seiler A. Wehnes H. Sinowatz F. Neumüller Walch A. M. F. A. M. M. et glutathione peroxidase 4 disruption causes male J. Biol. 2009; PubMed Scopus Google Scholar), our that mGPx4 is in photoreceptors. However, cGPx4 still also to photoreceptor survival photoreceptor observed in mGPx4 KO mice was that observed in photoreceptors of GPx4 T. T. T. Y. Nakagawa Y. Imai H. Y. Glutathione peroxidase 4 is for maturation of photoreceptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and of and a of for the retina the of the tissues in the of the PubMed Google Scholar). retina consists of types of and expression of as well as is the in the of the photoreceptors of the PubMed Google Scholar). with rod photoreceptors, cone photoreceptors a significantly mitochondrial of of the PubMed Google Scholar). In the mGPx4 KO mouse was in the cone photoreceptors and in the rod photoreceptors. the of the cell types of mGPx4 KO mouse retina was with the of In E supplementation was to rod photoreceptors and whereas cone photoreceptors not after with E indicate that cone photoreceptors to lipid in mitochondria which is with the role of in the loss of cone photoreceptors in Y. S. K. B. P.A. expression of glutathione peroxidase 4 retina 2009; PubMed Scopus Google Scholar, J. A. F. P.A. is a cause of cone cell death in PubMed Scopus Google Scholar). However, it the photoreceptor caused directly by mitochondrial lipid in photoreceptors or by in other cell types mGPx4 was in of the mGPx4 KO mice. in the by E for cone and rod photoreceptors by the of E through S. vitamin E is with in the but in the J. PubMed Scopus (21) Google and the that the into cone photoreceptors the into rod photoreceptors after the of to E cone and rod photoreceptors in their early cell in PubMed Scopus Google Scholar). In that GPx4 function as a of peroxidized in the mitochondria of spermatocytes (5Imai H. Hakkaku N. Iwamoto R. Suzuki J. Suzuki T. Tajima Y. Konishi K. Minami S. Ichinose S. Ishizaka K. Shioda S. Arata S. Nishimura M. Naito S. Nakagawa Y. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice.J. Biol. Chem. 2009; 284: 32522-32532Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, F. S. M. M. A. J. function of the selenoprotein PHGPx PubMed Scopus Google Scholar), which also the E supplementation in the of photoreceptors in mGPx4 KO mice. is of the major in the retina and rod and of in the Lipid Res. PubMed Scopus Google Scholar, J.P. role of in and of the Res. PubMed Scopus Google it is for the of photoreceptors and their survival H. H. J. H. H. Nakagawa Y. D. Y. F. H. S. T. T. acid function by in photoreceptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, photoreceptors are known to unique phospholipids esterified at and of the acid in in and other PubMed Scopus Google Scholar), which was also in the present the key roles by esterified to in lipid and ferroptosis M. H. B. Stockwell B.R. Regulation of lipid and ferroptosis in PubMed Scopus Google Scholar). in mGPx4 KO mouse we observed a significant increase in the of but significant in In addition, E supplementation the increase in peroxidized and ameliorated the and However, our by that the of mitochondria in mGPx4 KO mouse photoreceptors was which is not for ferroptosis in which mitochondria are prevent mitochondrial by and in cancer R. D. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Y. regulation in J. Cell Biol. PubMed Scopus Google Scholar, H. D. J. Y. R. H. ferroptosis and acute to and PubMed Scopus Google Scholar). In addition, we also observed uniformly and as well as caspase-3 activation in mGPx4 KO mouse photoreceptors, suggesting the of at in In ferroptosis, the of nuclei B.R. Angeli J.P. H. Conrad M. S. S. K. A. M.E. M. et A regulated cell death and Full Text Full Text PDF PubMed Scopus Google Scholar). are with in that mGPx4 and activation and cell death by apoptosis and H. Nakagawa Y. of phospholipid hydroperoxide glutathione peroxidase in mammalian Biol. 2003; PubMed Scopus Google Scholar, K. Imai H. Koumura T. M. Nakagawa Y. phospholipid hydroperoxide glutathione peroxidase apoptosis by a mitochondrial death Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). by the mitochondria in mGPx4 KO photoreceptors in and in which that mitochondria the of we observed of in the mGPx4 KO at the mitochondrial membrane and and it key roles in mitochondrial and the and A that mitochondrial and lipid and found that the of cancer to ferroptosis J. R. D. ferroptosis through mitochondrial Cell Biol. 9: PubMed Scopus Google Scholar). a role of to lipid and ferroptotic cell death in a cell S. T. N. Y. J. Y. S. by the and Res. PubMed Scopus Google Scholar). In addition, the other that relative lipid is with mitochondrial M. S. R. D. N. H. lipid directly with mitochondrial phenotype and in J. PubMed Scopus Google Scholar). these we in that the of in mGPx4 KO retina not mitochondrial but also lipid and photoreceptor death. other is that mitochondrial in mGPx4 KO mouse by the of a unique of and the increase of its which In conclusion, the the roles of GPx4 in the mitochondria for photoreceptor development and survival. mGPx4 is indispensable for cone photoreceptors at the early of their In rod photoreceptors although gradually afterward. the of mGPx4 KO cone and rod photoreceptors a phenotype cone–rod the mGPx4 KO the regulatory and regions a in the for mitochondrial GPx4 to and regions and and our mouse GPx4 (5Imai H. Hakkaku N. Iwamoto R. Suzuki J. Suzuki T. Tajima Y. Konishi K. Minami S. Ichinose S. Ishizaka K. Shioda S. Arata S. Nishimura M. Naito S. Nakagawa Y. Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice.J. Biol. Chem. 2009; 284: 32522-32532Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, H. Saito M. Kirai N. Hasegawa J. Konishi K. Hattori H. Nishimura M. Naito S. Nakagawa Y. Identification of the positive regulatory and distinct core regions of promoters, and transcriptional regulation in three types of mouse phospholipid hydroperoxide glutathione peroxidase.J. Biochem. (Tokyo). 2006; 140: 573-590Crossref PubMed Scopus (22) Google and into for GPx4 we the located after the in the GPx4 with A a of the to a for the to and to was in a at the for mitochondrial GPx4 with was into the of the the mGPx4 KO was with and by the for in and for the of in and by the of the of and in with and and to a at mGPx4 KO mice by as H. of functional of PHGPx mice and Biochem. PubMed Scopus Google Scholar). the was into mGPx4 KO mice by of the mice, the to was mice with GPx4 mice that we (2Imai H. Hirao F. Sakamoto T. Sekine K. Mizukura Y. Saito M. Kitamoto T. Hayasaka M. Hanaoka K. Nakagawa Y. Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene.Biochem. Biophys. Res. Commun. 2003; 305: 278-286Crossref PubMed Scopus (252) Google Scholar). Furthermore, GPx4 mice with GPx4 mice to GPx4 KO mice for for as for and for KO a mouse with mGPx4 KO GPx4 was and to as mGPx4 KO mice. mGPx4 KO mice male the mouse was by mGPx4 KO mice with male mice. as as mice to with their mGPx4 KO mGPx4 KO and mice in a with of of and for the male infertility and for the the of mGPx4 KO and mice, male mouse was with of for mice for and after three was of the with of the mice was in and with a and at for for the and mitochondrial membrane mitochondrial membrane by the of for and with for and with of and in was and with a mice and mGPx4 KO mice was in and in and with and in for and in in 4 at by for with at 4 and with for at with and Cell and GPx4 H. Suzuki K. Ishizaka K. Ichinose S. H. K. M. Nakagawa Y. of the expression of phospholipid hydroperoxide glutathione peroxidase in the of PubMed Scopus Google Scholar). and and for was of to cone In was for to the of in for and by for at 4 with for with a and with of was and in a of in was in a of in through a of and in with and and by at We of in of the and in at 4 with and with by a a the of mitochondria, we the of mitochondria of of and and mGPx4 KO and tissues and in and with was at for at 4 and the was as was with a for at 4 and the was at for at 4 was as was at for at 4 the was as was with as mitochondrial in cytosolic and mitochondrial the acid in 4 to or and to a membrane membrane was by for and was with at 4 of membrane by H. Suzuki K. Ishizaka K. Ichinose S. H. K. M. Nakagawa Y. of the expression of phospholipid hydroperoxide glutathione peroxidase in the of PubMed Scopus Google Scholar), Cell and Cell and of was a and for and for was in mice, and the was in mice. was after of to three for after to with a of for and at of and in to a as M. S. J. Sakamoto T. H. K. Y. A. Saito N. T. N. Y. Kobayashi K. S. H. et of cell ferroptosis in Commun. PubMed Scopus Google Scholar, T. K. Y. Imai H. of lipid the the of Biochem. PubMed Scopus Google Scholar). Y. of the for PubMed Scopus Google which is for is a of to functions in are as a with was to three was by considered to are the supporting that of with the of We and of for of mice, Ichinose of and for for and of the of for supporting was by for and for and and and for the of H. and T. U. T. S. M. H. and T. U. K. A. K. R. M. R. S. and T. U. T. K. and H. K. A. T. S. M. H. and T. U. T. S. M. H. and T. U. T. U. H. and T. U. with

Topics & Concepts