Role of mitochondria in toxic cell death.
Apoptosis is a highly regulated form of cell death distinguished by the activation of a family of cysteine-aspartate proteases (caspases) that cleave various proteins resulting in morphological and biochemical changes characteristic of this form of cell death. Abundant evidence supports a role for mitochondria in regulating apoptosis. Specifically, it seems that a number of death triggers target these organelles and stimulate, by an unknown mechanism, the release of several proteins, including cytochrome c. Once released into the cytosol, cytochrome c binds to its adaptor molecule, apoptotic protease activating factor-1, which oligomerizes and then activates pro-caspase-9. Caspase-9 can signal downstream and activate pro-caspase-3 and -7. The release of cytochrome c can be influenced by different Bcl-2 family member proteins, including Bax, Bid, Bcl-2, and Bcl-X(L). Bax and Bid potentiate cytochrome c release, whereas Bcl-2 and Bcl-X(L) antagonize this event. Although toxicologists have traditionally associated cell death with necrosis, emerging evidence suggests that different types of environmental contaminants exert their toxicity, at least in part, by triggering apoptosis. The mechanism responsible for eliciting the pro-apoptotic effect of a given chemical is often unknown, although in many instances mitochondria appear to be key participants. Here, we provide an overview of our current understanding of the role of apoptosis in toxicant-induced cell death, using dioxin, organotin compounds, dithiocarbamates, as well as the chemotherapeutic agent etoposide, as specific examples.
Robertson
John D
JD
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden.
Orrenius
Sten
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D009336:Necrosis; D015262:Xenobiotics / Q000633:toxicity
D004785:Environmental Pollutants; D015262:Xenobiotics; D020169:Caspases