Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 36, Issue 6, Pages 1437-1444Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo_00000629
Keywords
mitochondria; fission; calcium; prostate
Categories
Funding
- VA Merit Review
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Mitochondria are structurally complex organelles that undergo fragmentation or fission in apoptotic cells. Mitochondrial fission requires the cytoplasmic dynamin-related protein, Drp1, which translocates to the mitochondria during apoptosis and interacts with the mitochondrial protein, Fis1. Finely tuned changes in cellular calcium modulate a variety of intracellular functions; in resting cells, the level of mitochondrial calcium is low, while it is higher during apoptosis. Mitochondria take up Ca2+ via the Uniporter and extrude it to the cytoplasm through the mitochondrial Na+/Ca2+ exchanger. Overload of Ca2+ in the mitochondria leads to their damage, affecting cellular function and survival. The mitochondrial Na+/Ca2+ exchanger was blocked by benzodiazepine, CGP37157 (CGP) leading to increased mitochondrial calcium and enhancing the apoptotic effects of TRAIL, TNF alpha related apoptosis inducing ligand. In the present study, we observed that increasing mitochondrial calcium induced mitochondrial fragmentation, which correlated with the presence of Drp1 at the mitochondria in CGP treated cells. Under these conditions, we observed interactions between Drp1 and Fis1. The importance of Drp1 in fragmentation was confirmed by transfection of dominant negative Drp1 construct. However, fragmentation of the mitochondria was not sufficient to induce apoptosis, although it enhanced TRAIL-induced apoptosis. Furthermore, oligomerization of Bak was partially responsible for the increased apoptosis in cells treated with both COP and TRAIL. Thus, our results show that combination of an apoptogenic agent and an appropriate calcium channel blocker provide therapeutic advantages.
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