Reduced mitochondrial membrane potential and altered responsiveness of a mitochondrial membrane megachannel in p53-induced senescence.
There is accumulating evidence that mitochondrial membrane potential (DeltaPsi(M)) is reduced in aged cells. In addition, a decrease of DeltaPsi(M) has been shown to be an early event in many forms of apoptosis. Here we use a mitochondrial potentiometric dye with in situ laser scanning confocal microscopic (LSCM) imaging to demonstrate that DeltaPsi(M) is dramatically decreased in both the p53-overexpressing, senescent EJ tumor cells and in pre-apoptotic PC12 cells compared to controls. Treatment with cyclosporin A (CSA), which facilitates closure of the mitochondrial permeability transition pore (PTP), was able to reverse the decrease in DeltaPsi(M) in pre-apoptotic PC12 cells but not in the senescent EJ-p53 cells. The capacity to prevent dissipation of DeltaPsi(M) in response to agents that facilitate PTP closure may differentiate cells entering apoptosis from those participating in senescence. Therefore, regulation of the closure of the mitochondrial PTP in the presence of decreased DeltaPsi(M) may be a decisional checkpoint in distinguishing between growth arrest pathways.
Sugrue
M M
MM
Department of Pediatrics, Division of Hematology/Oncology, Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York, 10029-6574, USA. msugrue@smtplink.mssm.edu
Wang
Y
Y
Rideout
H J
HJ
Chalmers-Redman
R M
RM
Tatton
W G
WG
D000818:Animals; D017209:Apoptosis; D001710:Biotin / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D016922:Cellular Senescence; D016572:Cyclosporine / Q000494:pharmacology; D005456:Fluorescent Dyes; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D010539:Permeability; D051381:Rats; D012235:Rhodamines; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
C116572:(((4-chloromethyl)benzoyl)amino)-tetramethylrhodamine; D005456:Fluorescent Dyes; D007473:Ion Channels; D009414:Nerve Growth Factors; D012235:Rhodamines; D016159:Tumor Suppressor Protein p53; D001710:Biotin; D016572:Cyclosporine