Mitoparan and target-selective chimeric analogues: membrane translocation and intracellular redistribution induces mitochondrial apoptosis.
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.
Jones
Sarah
S
Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK. S.Jones4@wlv.ac.uk
Martel
Cecile
C
Belzacq-Casagrande
Anne-Sophie
AS
Brenner
Catherine
C
Howl
John
J
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000648:ultrastructure; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D014862:Wasp Venoms / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
D010455:Peptides; D014862:Wasp Venoms; C529760:mitoparan