TY - JOUR
T1 - Polyethylenimine-mediated impairment of mitochondrial membrane potential, respiration and membrane integrity
T2 - Implications for nucleic acid delivery and gene therapy
AU - Larsen, Anna K.
AU - Malinska, Dominika
AU - Koszela-Piotrowska, Izabela
AU - Parhamifar, Ladan
AU - Hunter, A. Christy
AU - Moghimi, S. Moein
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Mitochondrial membrane potential
KW - Mitochondrial swelling
KW - Polycations
KW - Polyethyleneimine
KW - Respiration
UR - http://www.scopus.com/inward/record.url?scp=84856537185&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856537185&partnerID=8YFLogxK
U2 - 10.1016/j.mito.2011.08.013
DO - 10.1016/j.mito.2011.08.013
M3 - Article
C2 - 21925619
AN - SCOPUS:84856537185
VL - 12
SP - 162
EP - 168
JO - Mitochondrion
JF - Mitochondrion
SN - 1567-7249
IS - 1
ER -