Sci. STKE, 19 October 2004
APOPTOSIS Breaking Up to Stay Alive
Mitochondria undergo continuous remodeling through fission and fusion, existing as a structurally dynamic network. Although mitochondrial fission is required for cell division, the more general functions of this constant structural remodeling are unclear. Mitochondrial fission also takes place during apoptosis, and Szabadkai et al. combined morphological analysis and calcium imaging with overexpression of the mitochondrial fission factor dynamin-related protein-1 (Drp-1) to investigate the relationship among mitochondrial fragmentation, calcium signaling, and apoptosis. In HeLa cells overexpressing Drp-1, both morphological analysis of mitochondria loaded with dye and fluorescence recovery after photobleaching analysis indicated that mitochondria underwent fragmentation, whereas the endoplasmic reticulum (ER, visualized with targeted green fluorescent protein) did not. Drp-1-dependent fragmentation limited the intramitochondrial diffusion of calcium waves and decreased the peak intramitochondrial calcium concentration in cells maximally stimulated with histamine, whereas cytosolic and ER calcium signals were unaffected. Analysis of the effects of submaximal histamine exposure indicated that this decrease in peak mitochondrial calcium resulted from heterogeneity of mitochondrial calcium uptake combined with the lack of free intramitochondrial diffusion. Drp-1 overexpression and mitochondrial fragmentation did not elicit cell death. Indeed, Drp-1 overexpressing cells were resistant to calcium-mediated apoptosis following treatment with ceramide and released less cytochrome c in response to serum deprivation or H2O2 treatment (which also promote calcium-dependent apoptosis). In marked contrast, Drp-1 overexpression increased sensitivity to staurosporine, which triggers apoptosis independently of calcium. Thus, the authors propose that regulated changes in mitochondrial morphology may limit calcium overload and help protect the cell from calcium-mediated apoptosis.
G. Szabadkai, A. M. Simoni, M. Chami, M. R. Wieckowski, R. J. Youle, R. Rizutto, Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. Molecular Cell 16, 59-68 (2004). [Online Journal]
Citation: Breaking Up to Stay Alive. Sci. STKE 2004, tw373 (2004).
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