Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells

Ismail Kaddour-Djebbar, Vivek Choudhary, Craig Brooks, Taghreed Ghazaly, Vijayabaskar Lakshmikanthan, Zheng Dong, M. Vijay Kumar

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Mitochondria are structurally complex organelles that undergo fragmentation or fission in apoptotic cells. Mitochondrial fission requires the cytoplasmic dynamin-related protein, Drp 1, which translocates to the mitochondria during apoptosis and interacts with the mitochondrial protein, Fis 1. 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+/Ca 2+ 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, TNFα related apoptosis inducing ligand. In the present study, we observed that increasing mitochondrial calcium induced mitochondrial fragmentation, which correlated with the presence of Drp 1 at the mitochondria in CGP treated cells. Under these conditions, we observed interactions between Drp 1 and Fis 1. The importance of Drp 1 in fragmentation was confirmed by transfection of dominant negative Drp 1 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.

Original languageEnglish (US)
Pages (from-to)1437-1444
Number of pages8
JournalInternational Journal of Oncology
Volume36
Issue number6
DOIs
StatePublished - Jun 1 2010

Fingerprint

Mitochondrial Dynamics
Prostatic Neoplasms
Mitochondria
Calcium
Apoptosis
Sodium-Calcium Exchanger
TNF-Related Apoptosis-Inducing Ligand
Dynamins
Mitochondrial Proteins
Calcium Channel Blockers
Benzodiazepines
Organelles
Transfection
Cytoplasm
7-chloro-5-(2-isopropylphenyl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one

Keywords

  • Calcium
  • Fission
  • Mitochondria
  • Prostate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells. / Kaddour-Djebbar, Ismail; Choudhary, Vivek; Brooks, Craig; Ghazaly, Taghreed; Lakshmikanthan, Vijayabaskar; Dong, Zheng; Kumar, M. Vijay.

In: International Journal of Oncology, Vol. 36, No. 6, 01.06.2010, p. 1437-1444.

Research output: Contribution to journalArticle

Kaddour-Djebbar, Ismail ; Choudhary, Vivek ; Brooks, Craig ; Ghazaly, Taghreed ; Lakshmikanthan, Vijayabaskar ; Dong, Zheng ; Kumar, M. Vijay. / Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells. In: International Journal of Oncology. 2010 ; Vol. 36, No. 6. pp. 1437-1444.
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