Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells.

Kaddour-Djebbar I, Choudhary V, Brooks C, Ghazaly T, Lakshmikanthan V, Dong Z, Kumar MV
Int J Oncol. 2010 36 (6): 1437-44

PMID: 20428767 · DOI:10.3892/ijo_00000629

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 Ca(2+) via the Uniporter and extrude it to the cytoplasm through the mitochondrial Na+/Ca(2+) exchanger. Overload of Ca(2+) 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, TNFalpha 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 CGP and TRAIL. Thus, our results show that combination of an apoptogenic agent and an appropriate calcium channel blocker provide therapeutic advantages.

MeSH Terms (21)

Apoptosis bcl-2 Homologous Antagonist-Killer Protein Blotting, Western Calcium Cell Line, Tumor Clonazepam GTP Phosphohydrolases Humans Immunohistochemistry Immunoprecipitation Male Membrane Proteins Microscopy, Electron, Transmission Microtubule-Associated Proteins Mitochondria Mitochondrial Proteins Prostatic Neoplasms Sodium-Calcium Exchanger Thiazepines TNF-Related Apoptosis-Inducing Ligand Transfection

Connections (1)

This publication is referenced by other Labnodes entities:

Links