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Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling.

ABSTRACT: Bid-induced mitochondrial membrane permeabilization and cytochrome c release are central to apoptosis. It remains a mystery how tiny amounts of Bid synchronize the function of a large number of discrete organelles, particularly in mitochondria-rich cells. Looking at cell populations, the rate and lag time of the Bid-induced permeabilization are dose-dependent, but even very low doses lead eventually to complete cytochrome c release. By contrast, individual mitochondria display relatively rapid and uniform kinetics, indicating that the dose dependence seen in populations is due to a spreading of individual events in time. We report that Bid-induced permeabilization and cytochrome c release regularly demonstrate a wave-like pattern, propagating through a cell at a constant velocity without dissipation. Such waves do not depend on caspase activation or permeability transition pore opening. However, reactive oxygen species (ROS) scavengers suppressed the coordination of cytochrome c release and also inhibited Bid-induced cell death, whereas both superoxide and hydrogen peroxide sensitized mitochondria to Bid-induced permeabilization. Thus, Bid engages a ROS-dependent, local intermitochondrial potentiation mechanism that amplifies the apoptotic signal as a wave.

SUBMITTER: Garcia-Perez C

PROVIDER: S-EPMC3311374 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling.

Garcia-Perez Cecilia C Roy Soumya Sinha SS Naghdi Shamim S Lin Xuena X Davies Erika E Hajnóczky György G

Proceedings of the National Academy of Sciences of the United States of America 20120305 12

Bid-induced mitochondrial membrane permeabilization and cytochrome c release are central to apoptosis. It remains a mystery how tiny amounts of Bid synchronize the function of a large number of discrete organelles, particularly in mitochondria-rich cells. Looking at cell populations, the rate and lag time of the Bid-induced permeabilization are dose-dependent, but even very low doses lead eventually to complete cytochrome c release. By contrast, individual mitochondria display relatively rapid a ...[more]

PMID: 22393005

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Project description:IntroductionThe use of flavors in electronic cigarettes appeals to adults and never-smoking youth. Consumption has rapidly increased over the last decade, and in the U.S. market alone, there are over 8000 unique flavors. The U.S. Food and Drug Administration (FDA) has begun to regulate e-liquids, but many have not been tested, and their impact, both at the cellular level, and on human health remains unclear.MethodsWe tested e-liquids on the human cell line HEK293T and measured toxicity, mitochondrial membrane potential (ΔΨ m), reactive oxygen species production (ROS), and cellular membrane potential (Vm) using high-throughput screening (HTS) approaches. Our HTS efforts included single-dose and 16-point dose-response curves, which allowed testing of ≥90 commercially available e-liquids in parallel to provide a rapid assessment of cellular effects as a proof of concept for a fast, preliminary toxicity method. We also investigated the chemical composition of the flavors via gas chromatography-mass spectrometry.ResultsWe found that e-liquids caused a decrease in ΔΨ m and Vm and an increase in ROS production and toxicity in a dose-dependent fashion. In addition, the presence of five specific chemical components: vanillin, benzyl alcohol, acetoin, cinnamaldehyde, and methyl-cyclopentenolone, but not nicotine, were linked with the changes observed in the cellular traits studied.ConclusionOur data suggest that ΔΨ m, ROS, Vm, and toxicity may be indicative of the extent of cell death upon e-liquid exposure. Further research on the effect of flavors should be prioritized to help policy makers such as the FDA to regulate e-liquid composition.ImplicationsE-liquid cellular toxicity can be predicted using parameters amenable to HTS. Our data suggest that ΔΨ m, ROS, Vm, and toxicity may be indicative of the extent of cell death upon e-liquid exposure, and this toxicity is linked to the chemical composition, that is, flavoring components. Further research on the effect of flavors should be prioritized to help policy makers such as the FDA to regulate e-liquid composition.

Dataset Information

Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling.

Publications

Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling.

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