title: Synergistic triggering of superoxide flashes by mitochondrial Ca2+ uniport and basal reactive oxygen species elevation.
abstract: Mitochondrial superoxide flashes reflect a quantal, bursting mode of reactive oxygen species (ROS) production that arises from stochastic, transient opening of the mitochondrial permeability transition pore (mPTP) in many types of cells and in living animals. However, the regulatory mechanisms and the exact nature of the flash-coupled mPTP remain poorly understood. Here we demonstrate a profound synergistic effect between mitochondrial Ca(2+) uniport and elevated basal ROS production in triggering superoxide flashes in intact cells. Hyperosmotic stress potently augmented the flash activity while simultaneously elevating mitochondrial Ca(2+) and ROS. Blocking mitochondrial Ca(2+) transport by knockdown of MICU1 or MCU, newly identified components of the mitochondrial Ca(2+) uniporter, or scavenging mitochondrial basal ROS markedly diminished the flash response. More importantly, whereas elevating Ca(2+) or ROS production alone was inefficacious in triggering the flashes, concurrent physiological Ca(2+) and ROS elevation served as the most powerful flash activator, increasing the flash incidence by an order of magnitude. Functionally, superoxide flashes in response to hyperosmotic stress participated in the activation of JNK and p38. Thus, physiological levels of mitochondrial Ca(2+) and ROS synergistically regulate stochastic mPTP opening and quantal ROS production in intact cells, marking the flash as a coincidence detector of mitochondrial Ca(2+) and ROS signals.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Hou
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.forename: Jiejia
authors.initials: J
authors.lastname: Xu
authors.forename: Chongshu
authors.initials: C
authors.lastname: Jian
authors.forename: Zhanglong
authors.initials: Z
authors.lastname: Huang
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Keping
authors.initials: K
authors.lastname: Hu
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured / Q000166:cytology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009995:Osmosis; D018384:Oxidative Stress; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D013481:Superoxides; D002118:Calcium