Calcium-independent Phospholipase A2 Localizes in and Protects Mitochondria during Apoptotic Induction by Staurosporine

Seleznev, Konstantin; Zhao, Chunli; Zhang, Xu Hannah; Song, Keying; Alex, Zhongmin

doi:10.1074/jbc.m604330200

Cited by 122 publications

(149 citation statements)

References 74 publications

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“…We observed 1.6-fold more apoptotic cells in G1 TERT-deficient MEFs than in wild-type MEFs upon STS treatment (Figure 2a). Consistently, we also found increased Annexin V-positive cells in TERT-deficient MEF cultures than were observed in wild-type MEF cultures (Figure 2b), using an Annexin V/propidium iodide (PI) double-staining assay (Seleznev et al, 2006). Moreover, when we measured cytochrome c release, we found increased cytochrome c release in TERT-deficient MEFs as compared to wild-type MEFs (Figure 2c).…”

supporting

confidence: 79%

TERT promotes cellular and organismal survival independently of telomerase activity

et al. 2008

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The expression level of the telomerase catalytic subunit (telomerase reverse transcriptase, TERT) positively correlates with cell survival after exposure to several lethal stresses. However, whether the protective role of TERT is independent of telomerase activity has not yet been clearly explored. Here, we genetically evaluated the protective roles of both TERT and telomerase activity against cell death induced by staurosporine (STS) and N-methyl-Daspartic acid (NMDA). First generation (G1) TERTdeficient mouse embryonic fibroblasts (MEFs) displayed an increased sensitivity to STS, while TERT transgenic MEFs were more resistant to STS-induced apoptosis than wildtype. Deletion of the telomerase RNA component (TERC) failed to alter the sensitivity of TERT transgenic MEFs to STS treatment. Similarly, NMDA-induced excitotoxic cell death of primary neurons was suppressed by TERT, but not by TERC both in vitro and in vivo. Specifically, NMDA accelerated death of TERT-deficient mice, while TERT transgenic mice showed enhanced survival when compared with wild-type littermates after administration of NMDA. In addition, the transgenic expression of TERT protected motor neurons from apoptosis induced by sciatic nerve axotomy. These results indicate that telomerase activity is not essential for the protective function of TERT. This telomerase activity-independent TERT function may contribute to cancer development and aging independently of telomere lengthening.

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confidence: 79%

TERT promotes cellular and organismal survival independently of telomerase activity

et al. 2008

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“…Although the evidence of lipid peroxidation in PAS-positive granules was not obtained, the increase of CL demonstrated by LC/ESI-MS/MS suggested insufficient remodeling of mitochondrial inner membranes in iPLA 2 ␤-KO mice. Oxidation of CL leads to subsequent loss of mitochondrial membrane potential and the release of cytochrome c and other apoptotic proteins (Seleznev et al, 2006). In fact, liver mitochondria isolated from iPLA 2 ␤-KO mice showed increased sensitivity to Ca 2ϩ overload, resulting in easy loss of membrane potential compared with those from control mice (our unpublished data).…”

Section: Discussionmentioning

confidence: 72%

“…Ultrastructurally, the mitochondrial and presynaptic membranes, both of which contain PC with DHA (Omoi et al, 2006;Mitchell et al, 2007), were affected, and tubulovesicular structures were formed in the middle and ends of axons. The vulnerability of mitochondrial and presynaptic membranes might be explained by the selective localization of iPLA 2 ␤ in mitochondria (Seleznev et al, 2006) and synapses (Ong et al, 2005). …”

Section: Discussionmentioning

confidence: 99%

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

Beck¹,

Sugiura²,

et al. 2011

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Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6[calcium-independent phospholipase A 2 ␤ (iPLA 2 ␤)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA 2 ␤ knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS)-positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acidcontaining phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA 2 ␤ deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA 2 ␤-KO mice.

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“…Phospholipases and acyl transferases/transacylases putatively involved in phospholipid remodeling have been localized to the endoplasmic reticulum, the Golgi, mitochondria, nucleus, and peroxisomes (9,10,18,51,52,(62)(63)(64)(65). It is an intriguing possibility that organelles harbor different sets of remodeling enzymes, which could contribute to their specific phospholipid molecular species profiles.…”

Section: Discussionmentioning

confidence: 99%

Electrospray Ionization Mass Spectrometry and Exogenous Heavy Isotope-labeled Lipid Species Provide Detailed Information on Aminophospholipid Acyl Chain Remodeling

Kainu

Hermansson

Somerharju

2008

Journal of Biological Chemistry

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Mammalian cells maintain the phospholipid compositions of their different membranes remarkably constant. Beside de novo synthesis, degradation, and intracellular trafficking, acyl chain remodeling plays an important role in phospholipid homeostasis. However, many key details of this process remain unresolved, largely because of limitations of existing methodologies. Here we describe a novel approach that allows one to study metabolism of individual phospholipid species in unprecedented detail. Forty different phosphatidylethanolamine (PE) or -serine (PS) species with a deuterium-labeled head group were synthesized and introduced to BHK21 or HeLa cells using cyclodextrin-mediated transfer. Their metabolism was then monitored in detail by electrospray ionization mass spectrometry. Atypical PE and PS species were rapidly remodeled at both sn1 and sn2 position, yielding a molecular species profile similar to that the endogenous PE and PS. In contrast, remodeling of exogenous species identical or similar to major endogenous ones was more limited and much slower. Major differences in remodeling pathways and kinetics were observed between species within a class, as well as between corresponding PE and PS species. These data along with those obtained with pharmacological inhibitors strongly suggest that multiple lipid class-specific A-type phospholipases and acyl transferases are involved in aminophospholipid remodeling. In conclusion, the approach described here provides highly detailed information on remodeling of exogenously added (amino)glycerophospholipids and should thus be very helpful when elucidating the proteins and processes maintaining molecular species homeostasis.

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Calcium-independent Phospholipase A2 Localizes in and Protects Mitochondria during Apoptotic Induction by Staurosporine

Cited by 122 publications

References 74 publications

TERT promotes cellular and organismal survival independently of telomerase activity

TERT promotes cellular and organismal survival independently of telomerase activity

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

Electrospray Ionization Mass Spectrometry and Exogenous Heavy Isotope-labeled Lipid Species Provide Detailed Information on Aminophospholipid Acyl Chain Remodeling

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Calcium-independent Phospholipase A2 Localizes in and Protects Mitochondria during Apoptotic Induction by Staurosporine

Cited by 122 publications

References 74 publications

TERT promotes cellular and organismal survival independently of telomerase activity

TERT promotes cellular and organismal survival independently of telomerase activity

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

Electrospray Ionization Mass Spectrometry and Exogenous Heavy Isotope-labeled Lipid Species Provide Detailed Information on Aminophospholipid Acyl Chain Remodeling

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Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes