title: Mechanisms underlying production and externalization of oxidized phosphatidylserine in apoptosis: involvement of mitochondria.
abstract: The present study was performed by using selective inhibitors of caspase-8 and caspase-3 functioning upstream and downstream from mitochondria, respectively to determine whether mitochondria are involved in the mechanisms underlying production and externalization of oxidized phosphatidylserine (PSox) during Fas-mediated apoptosis. Treatment with anti-Fas antibody induced caspase-3 activation, chromatin condensation, release of cytochrome c (cyt c) from mitochondria into the cytosol as well as production of PSox and its exposure to the cell surface in Jurkat cells. Inhibition of caspase-8 by pretreatment with Z-IETD-FMK, a membrane permeable selective caspase-8 inhibitor reduced mitochondrial cyt c release, the amount of PSox not only within but also on the surface of Jurkat cells, caspase-3 activation, and apoptotic cell number after treatment with anti-Fas antibody. In contrast, Z-DEVD-FMK, a membrane permeable selective caspase-3 inhibitor was unable to inhibit cyt c release, and the amount of PSox both within and on the surface of the cells after anti-Fas antibody, although it suppressed caspase-3 activation and apoptosis. Thus, these results strongly suggest that mitochondria play an important role in production of PSox and subsequent its externalization during apoptosis.
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Morikawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Tajima
authors.forename: Mari
authors.initials: M
authors.lastname: Teraoka
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kusumoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaso
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Matsura
keywords: apoptosis; caspase inhibitor; cytochrome c; mitochondria; oxidized phosphatidylserine
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