title: 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.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garcia-Perez
authors.forename: Soumya Sinha
authors.initials: SS
authors.lastname: Roy
authors.forename: Shamim
authors.initials: S
authors.lastname: Naghdi
authors.forename: Xuena
authors.initials: X
authors.lastname: Lin
authors.forename: Erika
authors.initials: E
authors.lastname: Davies
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000737:chemistry; D013997:Time Factors
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D017382:Reactive Oxygen Species; D013481:Superoxides; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D000263:Adenylate Kinase; D002118:Calcium