Previously it was known that cytosolic Ca2+ elevation was involved in regulating UV- or TNF alpha-induced apoptosis. Here, we reported new evidence that mitochondrial Ca2+ signal is also involved in the apoptotic process. First, using living cell imaging techniques, we observed multiple mitochondrial Ca2+ spikes during the early stage of UV- or TNF alpha-induced apoptosis. Second, the mitochondrial Ca2+ spikes were synchronous with cytosolic Ca2+ spikes observed in apoptosis, which preceded cytochrome c (cyt-c) release. Third, blocking the mitochondrial Ca2+ elevation by applying a mitochondrial uniporter inhibitor could suppress UV-induced apoptosis in HeLa cells. Finally, overexpressing an anti-apoptotic protein, Bcl-2, could suppress the mitochondrial Ca2+ elevation. Furthermore, it appeared that the elevation of mitochondrial Ca2+ during apoptosis was caused by a direct coupling between endoplasmic reticulum (ER) and mitochondria through IP3 receptors. Taken together, these findings suggest that Ca2+ mobilization from ER to mitochondria can play a significant role in the apoptotic signaling pathway. (C) 2008 Elsevier Inc. All rights reserved.