Low and high molecular weight poly(l-lysine)s/poly(l-lysine)–DNA complexes initiate mitochondrial-mediated apoptosis differently

Symonds, P., Murray, J.C., Hunter, A.C., Debska, G., Szewczyk, A. and Moghimi, S.M. (2005) Low and high molecular weight poly(l-lysine)s/poly(l-lysine)–DNA complexes initiate mitochondrial-mediated apoptosis differently Febs Letters, 579 (27). pp. 6191-6198. ISSN 0014-5793

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Abstract

Poly(l-lysine)s, PLLs, are commonly used for DNA compaction and cell transfection. We report that, although PLLs of low (2.9 kDa), L-PLL, and high (27.4 kDa), H-PLL, Mw in free form and DNA-complexed cannot only cause rapid plasma membrane damage in human cell lines, phosphatidylserine “scrambling” and loss of membrane integrity, but later (24 h) initiate stress-induced cell death via mitochondrial permeabilization without the involvement of processed caspase-2. Mitochondrially mediated apoptosis was confirmed by detection of cytochrome c (Cyt c) release, activation of caspases-9 and -3, and subsequent changes in mitochondrial membrane potential. Plasma membrane damage and apoptosis were most prominent with H-PLL. Cytoplasmic level of Cyt c was more elevated following H-PLL treatment, but unlike L-PLL case, inhibition of Bax channel-forming activity reduced the extent of Cyt c release from mitochondria by half. Inhibition of Bax channel-forming activity had no modulatory effect on L-PLL-mediated Cyt c release. Further, functional studies of isolated mitochondria indicate that H-PLL, but not L-PLL, can directly induce Cyt c release, membrane depolarization, and a progressive decline in the rate of uncoupled respiration. Combined, our data suggest that H-PLL and L-PLL are capable of initiating mitochondrially mediated apoptosis differently. The observed PLL-mediated late-phase apoptosis may provide an explanation for previously reported transient gene expression associated with PLL-based transfection vectors. The importance of our data in relation to design of novel and safer cationic non-viral vectors for human gene therapy is discussed.

Item Type: Journal article
Uncontrolled Keywords: Apoptosis; Bax channel; Gene transfer systems; Mitochondria; Phosphatidylserine; Polyamines; Poly(l-lysine); Poly(ethylenimine)
Subjects: A000 Medicine > A900 Medicine not elsewhere classified
B000 Health Professions
DOI (a stable link to the resource): 10.1016/j.febslet.2005.09.092
Faculties: Faculty of Science and Engineering > School of Pharmacy and Biomolecular Sciences > Biomedical Materials
Faculty of Science and Engineering > School of Pharmacy and Biomolecular Sciences > Chemical Biology
Faculty of Science and Engineering > School of Pharmacy and Biomolecular Sciences
Depositing User: editor spbs
Date Deposited: 08 Nov 2007
Last Modified: 05 Feb 2014 13:07
URI: http://eprints.brighton.ac.uk/id/eprint/666

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