Oxidation of phosphatidylserine: a mechanism for plasma membrane phospholipid scrambling during apoptosis?

Tyurina, Yulia Y.; Tyurin, Vladimir A.; Zhao, Qing; Djukić, Mirjana; Quinn, Peter J.; Pitt, Bruce R.; Kagan, Valerian E.

doi:10.1016/j.bbrc.2004.09.102

Cited by 86 publications

(60 citation statements)

References 18 publications

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“…(55)(56)(57)(58) Subsequently, oxidized PS cannot be maintained on the cytoplasmic side of the plasma membrane, possibly because of its enhanced diffusion within the membrane. (59) To test whether Ano6 specifically regulates calcium-dependent PS scrambling or if it also plays a role during oxidation-induced apoptotic PS exposure, we induced apoptosis in primary osteoblasts by treatment with the protein kinase inhibitor staurosporine. (60) At all time points analyzed, approximately 20%…”

Section: Regulation Of Ps Translocation In Osteoblasts By Ano6mentioning

confidence: 99%

Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues

Ehlen

Chinenkova

Moser

et al. 2012

Journal of Bone and Mineral Research

116

106

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During vertebrate skeletal development, osteoblasts produce a mineralized bone matrix by deposition of hydroxyapatite crystals in the extracellular matrix. Anoctamin6/Tmem16F (Ano6) belongs to a conserved family of transmembrane proteins with chloride channel properties. In addition, Ano6 has been linked to phosphatidylserine (PS) scrambling in the plasma membrane. During skeletogenesis, Ano6 mRNA is expressed in differentiating and mature osteoblasts. Deletion of Ano6 in mice results in reduced skeleton size and skeletal deformities. Molecular analysis revealed that chondrocyte and osteoblast differentiation are not disturbed. However, mutant mice display increased regions of nonmineralized, Ibsp-expressing osteoblasts in the periosteum during embryonic development and increased areas of uncalcified osteoid postnatally. In primary Ano6 À/À osteoblasts, mineralization is delayed, indicating a cell autonomous function of Ano6. Furthermore, we demonstrate that calcium-dependent PS scrambling is impaired in osteoblasts. Our study is the first to our knowledge to reveal the requirement of Ano6 in PS scrambling in osteoblasts, supporting a function of PS exposure in the deposition of hydroxyapatite. ß

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Section: Regulation Of Ps Translocation In Osteoblasts By Ano6mentioning

confidence: 99%

Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues

Ehlen

Chinenkova

Moser

et al. 2012

Journal of Bone and Mineral Research

116

106

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“…In the event asymmetry is altered, PtdSer is exposed to the cell surface, initiating early stages of apoptosis considered crucial to selective recognition and mononuclear phagocytosis of target cells by macrophages and fibroblasts (Castegna et al, 2004;Fadok et al, 2001;Tyurina et al, 2004b). Exposure of PtdSer to the outer leaflet has been noted to affect protein function involving platelet aggregation, activity of membrane receptors and transport proteins, signal transduction pathways, and cellular morphology via interference with lipidprotein and protein-protein interactions (Balasubramanian and Schroit, 2003;Paulusma and Oude Elferink, 2005;Verkleij and Post, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Oxidative stress and oxidative damage, hallmarks of Alzheimer disease (AD) pathology, can lead to increased production of lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein (2-propenal), in the membrane bilayer (Butterfield et al, 2001;Lovell et al, 2001;Markesbery and Lovell, 1998). These reactive alkenals have been found to interfere with PtdSer asymmetry via redox dependent flippase (Castegna et al, 2004;Daleke, 2003;Tyurina et al, 2004b). Furthermore, much evidence indicates that oxidative modification of flippase by reactive alkenals and/or apoptotic proteins, resulting in asymmetric collapse (Castegna et al, 2004;Kagan et al, 2002;Mandal et al, 2005;Mohmmad Abdul and Butterfield, 2005;Tyurina et al, 2004a), is greatly elevated in the early apoptotic phenotype of AD models (Herrmann and Devaux, 1990;Kagan et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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“…It is known that one of the first steps of cellular apoptosis involves PS oxidization in the fatty acyl chains that are recognized by macrophages receptors for the clearance of apoptotic cells [1][2][3]. Several studies showed that oxidized PS is preferentially recognized by macrophage scavenger receptors over non-oxidized PS [4][5][6][7]. The oxidation products of PS identified in vivo consisted of oxidative modifications in the fatty acyl chains, such as PS hydroxide and hydroperoxide derivatives and truncated sn-2 fatty acyl species [4,8,9].…”

Section: Introductionmentioning

confidence: 99%

Detection of phosphatidylserine with a modified polar head group in human keratinocytes exposed to the radical generator AAPH

Maciel

Neves

Santinha

et al. 2014

Archives of Biochemistry and Biophysics

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Phosphatidylserine (PS) is preferentially located in the inner leaflet of the cell membrane, and translocation of PS oxidized in fatty acyl chains to the outside of membrane has been reported as signaling to macrophage receptors to clear apoptotic cells. It was recently shown that PS can be oxidized in serine moiety of polar head-group. In the present work, a targeted lipidomic approach was applied to detecting OxPS modified at the polar head-group in keratinocytes that were exposed to the radical generator AAPH. Glycerophosphoacetic acid derivatives (GPAA) were found to be the major oxidation products of OxPS modified at the polar head-group during oxidation induced by AAPH-generated radicals, similarly to previous

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Oxidation of phosphatidylserine: a mechanism for plasma membrane phospholipid scrambling during apoptosis?

Cited by 86 publications

References 18 publications

Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues

Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Detection of phosphatidylserine with a modified polar head group in human keratinocytes exposed to the radical generator AAPH

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