Cadmium toxicity toward caspase-independent apoptosis through the mitochondria-calcium pathway in mtDNA-depleted cells

Yung Luen Shih, Chien Ju Lin, Sheng Wei Hsu, Sheng Hao Wang, Wei Li Chen, Mei Tsu Lee, Yau Huei Wei, Chwen Ming Shih

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Mitochondria are believed to be integrators and coordinators of programmed cell death in addition to their respiratory function. Using mitochondrial DNA (mtDNA)-depleted osteosarcoma cells (p0 cells) as a cell model, we investigated the apoptogenic signaling pathway of cadmium (Cd) under a condition of mitochondrial dysfunction. The apoptotic percentage was determined to be around 58.0% after a 24-h exposure to 25 μM Cd using flow cytometry staining with propidium iodine (PI). Pretreatment with Z-VAD-fmk, a broad-spectrum caspase inhibitor, failed to prevent apoptosis following Cd exposure. Moreover, Cd was unable to activate caspase 3 using DEVD-AFC as a substrate, indicating that Cd induced a caspase-independent apoptotic pathway in p0 cells. JC-1 staining demonstrated that mitochondrial membrane depolarization was a prelude to apoptosis. On the other hand, the intracellular calcium concentration increased 12.5-fold after a 2-h exposure to Cd. More importantly, the apoptogenic activity of Cd was almost abolished by ruthenium red, a mitochondrial calcium uniporter blocker. This led us to conclude that mtDNA-depleted cells provide an alternative pathway for Cd to conduct caspase-independent apoptosis through a mitochondria-calcium mechanism.

Original languageEnglish
Pages (from-to)497-505
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume1042
DOIs
Publication statusPublished - 2005

Fingerprint

Mitochondria
Caspases
Cadmium
Mitochondrial DNA
Toxicity
Apoptosis
Calcium
Staining and Labeling
Ruthenium Red
Caspase Inhibitors
Flow cytometry
Pathway
Cells
Propidium
Depolarization
Mitochondrial Membranes
Cell death
Osteosarcoma
Caspase 3
Iodine

Keywords

  • Apoptosis
  • Cadmium
  • Caspase
  • Miotochondria

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Cadmium toxicity toward caspase-independent apoptosis through the mitochondria-calcium pathway in mtDNA-depleted cells. / Shih, Yung Luen; Lin, Chien Ju; Hsu, Sheng Wei; Wang, Sheng Hao; Chen, Wei Li; Lee, Mei Tsu; Wei, Yau Huei; Shih, Chwen Ming.

In: Annals of the New York Academy of Sciences, Vol. 1042, 2005, p. 497-505.

Research output: Contribution to journalArticle

Shih, Yung Luen ; Lin, Chien Ju ; Hsu, Sheng Wei ; Wang, Sheng Hao ; Chen, Wei Li ; Lee, Mei Tsu ; Wei, Yau Huei ; Shih, Chwen Ming. / Cadmium toxicity toward caspase-independent apoptosis through the mitochondria-calcium pathway in mtDNA-depleted cells. In: Annals of the New York Academy of Sciences. 2005 ; Vol. 1042. pp. 497-505.
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