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The Journal of Neuroscience, February 1, 1998, 18(3):932-947

Mitochondrial Membrane Potential and Nuclear Changes in Apoptosis Caused by Serum and Nerve Growth Factor Withdrawal: Time Course and Modification by ()-Deprenyl

J. S. Wadia¹, R. M. E. Chalmers-Redman^{2, 3}, W. J. H. Ju², G. W. Carlile², J. L. Phillips², A. D. Fraser^{2, 3}, and W. G. Tatton^{2, 3}

¹ Department of Physiology, University of Toronto, Toronto, Ontario, Canada M55 1A8, ² Department of Physiology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7, and ³ Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029-6511

Studies in non-neural cells have suggested that a fall in mitochondrial membrane potential (_M) is one of the earliest events in apoptosis. It is not known whether neural apoptosis caused by nerve growth factor (NGF) and serum withdrawal involves a decrease in _M. We used epifluorescence and laser confocal microscopy with the mitochondrial potentiometric dyes chloromethyl-tetramethylrosamine methyl ester and 5,5,6,6-tetrachloro-1,1,3,3-tetraethybenzimidazol carbocyanine iodide to estimate _M. PC12 cells were differentiated in media containing serum and NGF for 6 d before withdrawal of trophic support. After washing, the cells were incubated with media containing serum and NGF (M/S+N), media without serum and NGF, or media with the "trophic-like" monoamine oxidase B inhibitor, ()-deprenyl. Mitochondria in cells without trophic support underwent a progressive shift to lower _M values that was significant by 3 hr after washing. The percentages of cells with nuclear chromatin condensation or nuclear DNA fragmentation were not significantly increased above those for cells in M/S+N until 6 hr after washing. Replacement of cells into M/S+N or treatment with ()-deprenyl markedly reduced the proportion of mitochondria with decreased _M. Measurements of cytoplasmic peroxyl radical levels with 2,7-dihydrodichlorofluorescein fluorescence and intramitochondrial Ca²⁺ with dihydro-rhodamine-2-acetylmethyl ester indicated that cytoplasmic peroxyl radical levels were not increased until after 6 hr, whereas increases in intramitochondrial Ca²⁺ paralleled the decreases in _M. ()-Deprenyl appeared to alter the relationship between intramitochondrial Ca²⁺ levels and _M, possibly through its reported capacity to increase the synthesis of proteins such as BCL-2.

Key words: apoptosis; mitochondrial membrane potential; DNA cleavage; chromatin condensation; JC-1; CMTMR; Rhod-2AM; DCFH

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Copyright © 1998 Society for Neuroscience  0270-6474/98/183932-16$05.00/0

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