Cadmium Toxicity toward Caspase-Independent Apoptosis through the Mitochondria-Calcium Pathway in mtDNA-Depleted Cells

• Published in: Annals of the New York Academy of Sciences Vol. 1042; no. 1; pp. 497 - 505
• Main Authors: SHIH, YUNG-LUEN, LIN, CHIEN-JU, HSU, SHENG-WEI, WANG, SHENG-HAO, CHEN, WEI-LI, LEE, MEI-TSU, WEI, YAU-HUEI, SHIH, CHWEN-MING
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2005
• Subjects: Apoptosis; Apoptosis - drug effects; Cadmium; Cadmium - toxicity; Calcium; Calcium Signaling; caspase; Caspase Inhibitors; Caspases - metabolism; Cell Line, Tumor; Cell Polarity - drug effects; DNA, Mitochondrial - genetics; Enzyme Inhibitors - pharmacology; Flow cytometry; Gene Deletion; Humans; Inhibitors; Membrane Potentials - drug effects; miotochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membranes - drug effects; Pathways; Staining; Toxicity
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1196/annals.1338.043

: 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 (ρ0 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 ρ0 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.