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J Biol Chem, Vol. 274, Issue 47, 33267-33273, November 19, 1999

Modulation of Mitochondrial Ca2+ Homeostasis by Bcl-2

Liping ZhuDagger , Song LingDagger , Xiao-Dan YuDagger , L. K. Venkatesh§, T. Subramanian§, G. Chinnadurai§, and Tuan H. KuoDagger

From the Dagger  Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201 and the § Institute for Molecular Virology, St. Louis University Medical Center, St. Louis, Missouri 63110

We have investigated the role of mitochondrial Ca2+ (Cam) homeostasis in cell survival. Disruption of Cam homeostasis via depletion of the mitochondrial Ca2+ store was the earliest event that occurred during staurosporine-induced apoptosis in neuroblastoma cells (SH-SY5Y). The decrease of Cam preceded activation of the caspase cascade and DNA fragmentation. Overexpression of the anti-apoptosis protein Bcl-2 led to increased Cam load, increased mitochondrial membrane potential (Delta Psi m), and inhibition of staurosporine-induced apoptosis. On the other hand, ectopic expression of the pro-apoptotic protein Bik led to decreased Cam load and decreased Delta Psi m. Inhibition of calcium uptake into mitochondria by ruthenium red induced a dose-dependent apoptosis as determined by nuclear staining and DNA ladder assay. Similarly, reducing the Cam load by lowering the extracellular calcium concentration also led to apoptosis. We suggest that the anti-apoptotic effect of Bcl-2 is related to its ability to maintain a threshold level of Cam and Delta Psi m while the pro-apoptotic protein Bik has the opposite effect. Furthermore, both ER and mitochondrial Ca2+ stores are important, and the depletion of either one will result in apoptosis. Thus, our results, for the first time, provide evidence that the maintenance of Cam homeostasis is essential for cell survival.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.


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