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First published online 19 February 2003
doi: 10.1242/jcs.00320

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Journal of Cell Science 116, 1437-1447 (2003)
doi: 10.1242/jcs.00320

Research Article

Two phases of signalling between mitochondria during apoptosis leading to early depolarisation and delayed cytochrome c release

May-Ghee Lum and Phillip Nagley*

Department of Biochemistry and Molecular Biology, PO Box 13D, Monash University, Victoria 3800, Australia

* Author for correspondence (e-mail: phillip.nagley{at}med.monash.edu.au)

Accepted 12 December 2002

We investigated the mode of signalling between mitochondria during apoptosis by monitoring the behaviour of non-irradiated mitochondria following microscopic photosensitisation of half the mitochondria in single human osteosarcoma cells loaded with CMXRos. Following partial irradiation of cells, non-irradiated mitochondria underwent a rapid depolarisation (within 10 minutes). The depolarisation was not inhibited by the caspase inhibitor zVAD-fmk but was suppressed by the intracellular Ca2+ chelator BAPTA and overexpression of Bcl-2. Significantly, such depolarisation occurred even after prior conversion of extended filamentous mitochondria into individual punctate structures, indicating that lumenal continuity is not required for communication between the irradiated and non-irradiated mitochondria. Partial irradiation of cells expressing cytochrome c-GFP revealed cytochrome c-GFP release from non-irradiated mitochondria at a delayed but unpredictable time interval (between 30 minutes and more than 2.5 hours) following irradiation, which was unaffected by zVAD-fmk. Once activated, cytochrome c-GFP release occurred within a 10 minute period. Immunocytochemistry failed to reveal the recruitment of Bax to non-irradiated mitochondria, which suggests that Bax does not mediate the release of cytochrome c from mitochondria. We conclude that signals (mediated by Ca2+) emanating from irradiated mitochondria are processed by their non-irradiated counterparts and comprise two temporally distinct phases, both independent of caspase-mediated amplification, which generate an initial rapid depolarisation and subsequent delayed release of cytochrome c.

Key words: Apoptosis, Mitochondria, Photosensitisation, Confocal microscopy, Chloromethyl-X-Rosamine




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[Abstract] [Full Text] [PDF]


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