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Mitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis.
Jones, Sarah Martel, Cecile Belzacq-Casagrande, Anne-Sophie Brenner, Catherine Howl, John D.
Jones, Sarah
Martel, Cecile
Belzacq-Casagrande, Anne-Sophie
Brenner, Catherine
Howl, John D.
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Epub Date
Issue Date
2008
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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
Research Unit
PubMed ID
18267123
PubMed Central ID
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Type
Journal article
Language
en
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Series/Report no.
ISSN
0006-3002