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Irradiation of mitochondria initiates apoptosis in a cell free system

Oncogene volume 20, pages 167–177 (2001)Cite this article

Abstract

The ability to modulate the sensitivity of mammalian cells to ionizing radiation (IR) (e.g. using chemotherapeutics) is dependent on our understanding of the primary target and biochemical pathway that leads to IR-induced apoptosis. We demonstrate using a cell free assay that irradiation of mitochondria is a primary event that initiates IR-induced apoptosis. IR results in loss of mitochondrial membrane potential, opening of the permeability transition pore (PTP) and the release of cytochrome c (cyto c). Apaf-1 and ATP were required to initiate apoptosis upon release of cyto c from mitochondria. The importance of mitochondrial events in the initiation of IR-induced apoptosis was also supported by the observation that inhibition of caspase-9 by the over-expression of dominant negative mutants resulted in the inhibition of IR-induced apoptosis. In contrast, inhibition of caspase-8 had only a minor impact on IR-induced apoptosis. Over-expression of Bcl-XL inhibited the initiation of IR-induced apoptosis due to its ability to prevent the loss of mitochondrial membrane potential, PTP opening and cytochrome c release. In a cell free assay for apoptosis, mitochondria as well as cytosol derived from Bcl-XL over-expressing cells were less efficient at supporting apoptosis in response to IR suggesting multiple roles for Bcl-XL in the regulation of apoptosis.

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Acknowledgements

We would like to acknowledge Amy Pace for help with preparation of figures. This work was partly supported by the UMCC (G00351 to N Taneja), the NIH (CA 78041 to A Rehemtulla) and the MDRTC, University of Michigan (ES 08846 to MA Philbert).

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, 48109, Michigan, MI, USA

    N Taneja & A Rehemtulla

  2. Department of Environmental Health Sciences, Toxicology Program, University of Michigan, Ann Arbor, 48109, Michigan, MI, USA

    R Tjalkens & MA Philbert

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  1. N Taneja
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  4. A Rehemtulla
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Taneja, N., Tjalkens, R., Philbert, M. et al. Irradiation of mitochondria initiates apoptosis in a cell free system. Oncogene 20, 167–177 (2001). https://doi.org/10.1038/sj.onc.1204054

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