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Molecular and Cellular Biology, January 2003, p. 665-676, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.665-676.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Susceptibility of Lysosomes to Rupture Is a Determinant for Plasma Membrane Disruption in Tumor Necrosis Factor Alpha-Induced Cell Death

Koh Ono, Sung O. Kim, and Jiahuai Han*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Received 15 August 2002/ Returned for modification 18 September 2002/ Accepted 22 October 2002

Since a release of intracellular contents can induce local inflammatory responses, mechanisms that lead to loss of plasma membrane integrity in cell death are important to know. We showed previously that deficiency of the plasma membrane Ca2+ ATPase 4 (PMCA4) in L929 cells impaired tumor necrosis factor alpha (TNF-{alpha})-induced enlargement of lysosomes and reduced cell death. The lysosomal changes can be determined by measuring the total volume of intracellular acidic compartments per cell (VAC), and we show here that inhibition of the increase in VAC due to PMCA4 deficiency not only reduced cell death but also converted TNF-{alpha}-induced cell death from a process involving disruption of the plasma membrane to a cell demise with a nearly intact plasma membrane. The importance of the size of lysosomes in determining plasma membrane integrity during cell death was supported by the observations that chemical inhibitors that reduce VAC also reduced the plasma membrane disruption induced by TNF-{alpha} in wild-type L929 cells, while increases in VAC due to genetic mutation, senescence, cell culture conditions, and chemical inhibitors all changed the morphology of cell death from one with an originally nearly intact plasma membrane to one with membrane disruption in a number of different cells. Moreover, the ATP depletion-mediated change from apoptosis to necrosis is also associated with the increases of VAC. The increase in lysosomal size may due to intracellular self-digestion of dying cells. Big lysosomes are easy to rupture, and the release of hydrolytic enzymes from ruptured lysosomes can cause plasma membrane disruption.

* Corresponding author. Mailing address: Department of Immunology IMM-32, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8704. Fax: (858) 784-8665. E-mail: jhan{at}scripps.edu.

Molecular and Cellular Biology, January 2003, p. 665-676, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.665-676.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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