Polyethylenimine-mediated impairment of mitochondrial membrane potential, respiration and membrane integrity: Implications for nucleic acid delivery and gene therapy

Anna K. Larsen, Dominika Malinska, Izabela Koszela-Piotrowska, Ladan Parhamifar, A. Christy Hunter, S. Moein Moghimi

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The 25. kDa branched polyethylenimine (PEI) is a highly efficient synthetic polycation used in transfection protocols, but also triggers mitochondrial-mediated apoptotic cell death processes where the mechanistic issues are poorly understood. We now demonstrate that PEI in a concentration- and time-dependent manner can affect functions (membrane potential, swelling and respiration) and ultrastructural integrity of freshly isolated rat liver mitochondria. The threshold concentration for detection of PEI-mediated impairment of rat liver mitochondrial functions is 3. μg/mL, however, lower PEI levels still exert some effects on mitochondrial morphology and respiration, and these may be related to the inherent membrane perturbing properties of this polycation. The PEI-mediated mitochondrial swelling phase is biphasic, with a fast decaying initial period (most prominent from 4. μg/mL PEI) followed by a slower, linear swelling response. The slow phase is presumably the result of a time-dependent transition permeability opening in mitochondria initially resistant to swelling/depolarization, but may further be related to PEI-induced nanoscale structural defects and/or formation of pores in the outer membrane. Respiration assessments further suggested that PEI in the presence of exogenous ADP behaves in a similar fashion to a slow-acting inhibitory compound. PEI further shows an uncoupling property that is detectable at low respiration rates. The relevance of these findings to PEI-mediated initiation of intrinsic apoptotic pathway is discussed.

Original languageEnglish (US)
Pages (from-to)162-168
Number of pages7
JournalMitochondrion
Volume12
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Apoptosis
  • Mitochondrial membrane potential
  • Mitochondrial swelling
  • Polycations
  • Polyethyleneimine
  • Respiration

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Molecular Medicine

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