title: Superoxide flashes: early mitochondrial signals for oxidative stress-induced apoptosis.
abstract: Irreversible mitochondrial permeability transition and the resultant cytochrome c release signify the commitment of a cell to apoptotic death. However, the role of transient MPT (tMPT) because of flickering opening of the mitochondrial permeability transition pore remains elusive. Here we show that tMPT and the associated superoxide flashes (i.e. tMPT/superoxide flashes) constitute early mitochondrial signals during oxidative stress-induced apoptosis. Selenite (a ROS-dependent insult) but not staurosporine (a ROS-independent insult) stimulated an early and persistent increase in tMPT/superoxide flash activity prior to mitochondrial fragmentation and a global ROS rise, independently of Bax translocation and cytochrome c release. Selectively targeting tMPT/superoxide flash activity by manipulating cyclophilin D expression or scavenging mitochondrial ROS markedly impacted the progression of selenite-induced apoptosis while exerting little effect on the global ROS response. Furthermore, the tMPT/superoxide flash served as a convergence point for pro- and anti-apoptotic regulation mediated by cyclophilin D and Bcl-2 proteins. These results indicate that tMPT/superoxide flashes act as early mitochondrial signals mediating the apoptotic response during oxidative stress, and provide the first demonstration of highly efficacious local mitochondrial ROS signaling in deciding cell fate.
authors.affiliation: Joint Laboratory of Apoptosis and Cancer Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Fang
authors.forename: Wei
authors.initials: W
authors.lastname: Shang
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Zhengshuang
authors.initials: Z
authors.lastname: Xu
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: D017209:Apoptosis; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D034622:RNA Interference; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*
chemical_list: D013481:Superoxides