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Phosphatidylserine peroxidation during apoptosis: a signaling pathway for phagocyte clearance.

Tyurina-Y; Tyurin-V; Liu-S; Smith-C; Shvedova-A; Schor-N; Kagan-V
Phospholipid Metabolism in Apoptosis, Subcellular Biochemistry. Kagan VE, Quinn PJ, eds., New York: Kluwer Academic/Plenum Publishers, 2002 Apr; 36:79-96
Two distinct pathways, apoptosis and necrosis, may be triggered contemporaneously or independently of each other to cause cell death. Necrotic cell death is generally a consequence of severe stress conditions resulting in increase in the cell volume, disruption of plasma membrane, release of intracellular contents and an inflammatory response. Apoptosis, or programmed cell death, is essential for normal tissue development and organogenesis, immunologic selection, response to tissue injury. It is characterized by chromatin condensation, DNA fragmentation, cytochrome c release, caspase activation and cell shrinkage. Our understanding of apoptosis initiation and execution pathways and mechanisms is far from being complete. In the nematode Caenorhabditis elegans, genetic studies resulted in the discovery of 15 genes that are essential for the apoptotic program. Some of these genes have been shown to be conserved across a wide range of species. These 15 genes have been divided into four groups based on temporal order of their action during apoptosis. The products of these genes are involved in: a) decision making (ces-1 and ces-2); b) execution (ced-3, ced-4, ced-9 and egl-1); c) engulfment of apoptotic cells (ced-1, ced-2, ced-5, ced-6, ced-7, ced-10, ced-12) and d) degradation of apoptotic cells within phagocytes (Wu and Horvitz, 1988 ab; Liu et al., 1999). Removal of apoptotic, damaged and other unwanted cells from the bloodstream or tissues, is very important for cell and tissue homeostasis. In vivo, apoptotic cells are efficiently removed by professional phagocytes, macrophages or neighboring cells acting as semi-professional phagocytes (Terpstra and Berkel, 2000; Chang et al., 2000; Witting et al., 2000). The mechanisms by which phagocytes recognize apoptotic cells are poorly understood. It is clear that the outer leaflet of plasma membrane in apoptotic cells must be different from that of healthy cells. Promotion of "safe" phagocytic clearance of cells undergoing apoptosis requires the appearance of cell surface "eat-me" signals on the apoptotic cells (Savill, 1998, Ren and Savill, 1998, Savill and Fadok, 2000). Some of the "eat-me" signals, such as changes in surface carbohydrate moieties of membrane proteins and exposure of phosphatidylserine (PS) on the surface of apoptotic cells, are well characterized (Dini et al., 1992; Benner et al., 1995; Martin et al., 1995; Adayev et al., 1998, Savill, 1997, 1998, Savill and Fadok, 2000; Witting et al., 2000). Other signals involved in the removal of apoptotic cells are not well characterized. These particular signals execute removal through adhesive bridging with extracellular matrix proteins that appear on apoptotic target cells. Execution of the apoptotic program is associated with departure of cytochrome c from mitochondria and disruption of electron transport resulting in generation of reactive oxygen species (ROS), particularly superoxide and hydrogen peroxide. Whether this ROS production during apoptosis is an inevitable but unimportant consequence of dysregulated electron transport, or fulfills important signaling functions during apoptosis, is not fully understood. Recently, formation of various ROS has been implicated as components of the final common pathway leading to the execution of apoptosis following exposure to tumor necrosis factor, growth factor withdrawal, various oxidants, and numerous other insults. It has been established that apoptosis and PS externalization are associated with ROS generation (Wood and Youle, 1994; Jacobson, 1996). Thus, appearance of PS in outer monolayer of the plasma membrane could be related to its oxidation in the plasma membrane of apoptotic cells. Thus, oxidized PS on the cell surface may be recognized as an "eat-me" signal by macrophages and serve to regulate and stimulate phagocytosis of apoptotic cells (Kagan et al., 2000).
Peroxides; Cell-morphology; Cell-damage; Cellular-reactions; Plasma-membrane; Genes; Genotoxic-effects
Publication Date
Document Type
Book or book chapter
Quinn-VE; Kagan-PJ
Fiscal Year
NIOSH Division
Source Name
Phospholipid Metabolism in Apoptosis, Subcellular Biochemistry
Page last reviewed: May 5, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division