title: Identification of EFHD1 as a novel Ca(2+) sensor for mitoflash activation.
abstract: Mitochondrial flashes (mitoflashes) represent stochastic and discrete mitochondrial events that each comprises a burst of superoxide production accompanied by transient depolarization and matrix alkalinization in a respiratory mitochondrion. While mitochondrial Ca(2+) is shown to be an important regulator of mitoflash activity, little is known about its specific mechanism of action. Here we sought to determine possible molecular players that mediate the Ca(2+) regulation of mitoflashes by screening mitochondrial proteins containing the Ca(2+)-binding motifs. In silico analysis and targeted siRNA screening identified four mitoflash activators (MICU1, EFHD1, SLC25A23, SLC25A25) and one mitoflash inhibitor (LETM1) in terms of their ability to modulate mitoflash response to hyperosmotic stress. In particular, overexpression or down-regulation of EFHD1 enhanced or depressed mitoflash activation, respectively, under various conditions of mitochondrial Ca(2+) elevations. Yet, it did not alter mitochondrial Ca(2+) handling, mitochondrial respiration, or ROS-induced mitoflash production. Further, disruption of the two EF-hand motifs of EFHD1 abolished its potentiating effect on the mitoflash responses. These results indicate that EFHD1 functions as a novel mitochondrial Ca(2+) sensor underlying Ca(2+)-dependent activation of mitoflashes.
authors.affiliation: State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: Chongshu
authors.initials: C
authors.lastname: Jian
authors.affiliation: State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: Jiejia
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
authors.forename: August Yue
authors.initials: AY
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Xi
authors.affiliation: Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Keping
authors.initials: K
authors.lastname: Hu
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. Electronic address: xianhua@pku.edu.cn.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C000614369:EFHD1 protein, human; D017382:Reactive Oxygen Species; D002118:Calcium
keywords: Ca(2+)-Binding proteins; EFHD1; Mitochondria; Mitochondrial Ca(2+) signaling; Mitochondrial flash (mitoflash)