Mitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis.

2.50
Hdl Handle:
http://hdl.handle.net/2436/30272
Title:
Mitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis.
Authors:
Jones, Sarah; Martel, Cecile; Belzacq-Casagrande, Anne-Sophie; Brenner, Catherine; Howl, John D.
Abstract:
Mastoparan, and structurally-related amphipathic peptides, may induce cell death by augmentation of necrotic and/or apoptotic pathways. To more precisely delineate cytotoxic mechanisms, we determined that [Lys(5,8)Aib(10)]mastoparan (mitoparan) specifically induces apoptosis of U373MG and ECV304 cells, as demonstrated by endonuclease and caspase-3 activation and phosphatidylserine translocation. Live cell imaging confirmed that, following translocation of the plasma membrane, mitoparan specifically co-localizes with mitochondria. Complementary studies indicated that mitoparan induces swelling and permeabilization of isolated mitochondria, through cooperation with a protein of the permeability transition pore complex VDAC, leading to the release of the apoptogenic factor, cytochrome c. N-terminal acylation of mitoparan facilitated the synthesis of chimeric peptides that incorporated target-specific address motifs including an integrin-specific RGD sequence and a Fas ligand mimetic. Significantly, these sychnologically-organised peptides demonstrated further enhanced cytotoxic potencies. We conclude that the cell penetrant, mitochondriotoxic and apoptogenic properties of mitoparan, and its chimeric analogues, offer new insights to the study and therapeutic induction of apoptosis.
Citation:
Biochimica et Biophysica Acta - Molecular Cell Research, 1783(5): 849-863
Publisher:
Amsterdam: Elsevier
Journal:
Biochimica et Biophysica Acta - Molecular Cell Research
Issue Date:
2008
URI:
http://hdl.handle.net/2436/30272
DOI:
10.1016/j.bbamcr.2008.01.009
PubMed ID:
18267123
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T20-4RP0MF4-1&_user=10&_coverDate=05%2F31%2F2008&_rdoc=17&_fmt=high&_orig=browse&_srch=doc-info(%23toc%234904%232008%23982169994%23686190%23FLA%23display%23Volume)&_cdi=4904&_sort=d&_docanchor=&_ct=26&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=78ecb320a945265feb7eb85cf01981e6
Type:
Article
Language:
en
ISSN:
0006-3002
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorJones, Sarah-
dc.contributor.authorMartel, Cecile-
dc.contributor.authorBelzacq-Casagrande, Anne-Sophie-
dc.contributor.authorBrenner, Catherine-
dc.contributor.authorHowl, John D.-
dc.date.accessioned2008-06-20T16:10:51Z-
dc.date.available2008-06-20T16:10:51Z-
dc.date.issued2008-
dc.identifier.citationBiochimica et Biophysica Acta - Molecular Cell Research, 1783(5): 849-863en
dc.identifier.issn0006-3002-
dc.identifier.pmid18267123-
dc.identifier.doi10.1016/j.bbamcr.2008.01.009-
dc.identifier.urihttp://hdl.handle.net/2436/30272-
dc.description.abstractMastoparan, and structurally-related amphipathic peptides, may induce cell death by augmentation of necrotic and/or apoptotic pathways. To more precisely delineate cytotoxic mechanisms, we determined that [Lys(5,8)Aib(10)]mastoparan (mitoparan) specifically induces apoptosis of U373MG and ECV304 cells, as demonstrated by endonuclease and caspase-3 activation and phosphatidylserine translocation. Live cell imaging confirmed that, following translocation of the plasma membrane, mitoparan specifically co-localizes with mitochondria. Complementary studies indicated that mitoparan induces swelling and permeabilization of isolated mitochondria, through cooperation with a protein of the permeability transition pore complex VDAC, leading to the release of the apoptogenic factor, cytochrome c. N-terminal acylation of mitoparan facilitated the synthesis of chimeric peptides that incorporated target-specific address motifs including an integrin-specific RGD sequence and a Fas ligand mimetic. Significantly, these sychnologically-organised peptides demonstrated further enhanced cytotoxic potencies. We conclude that the cell penetrant, mitochondriotoxic and apoptogenic properties of mitoparan, and its chimeric analogues, offer new insights to the study and therapeutic induction of apoptosis.en
dc.language.isoenen
dc.publisherAmsterdam: Elsevieren
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T20-4RP0MF4-1&_user=10&_coverDate=05%2F31%2F2008&_rdoc=17&_fmt=high&_orig=browse&_srch=doc-info(%23toc%234904%232008%23982169994%23686190%23FLA%23display%23Volume)&_cdi=4904&_sort=d&_docanchor=&_ct=26&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=78ecb320a945265feb7eb85cf01981e6en
dc.subjectPeptidesen
dc.subjectChimerismen
dc.subjectMastoparanen
dc.subjectMitochondriaen
dc.subjectApoptosisen
dc.subjectPeptide Mastoparanen
dc.subjectCell Penetrating Peptides (CPP)en
dc.subjectApoptosisen
dc.subjectCPPen
dc.subjectCytotoxicityen
dc.subjectMolecular Biologyen
dc.titleMitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis.en
dc.typeArticleen
dc.identifier.journalBiochimica et Biophysica Acta - Molecular Cell Researchen

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