title: Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity.
abstract: Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critical modulatory role for VDAC2-dependent mitochondrial Ca(2+) uptake in the regulation of cardiac rhythmicity.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Johann
authors.initials: J
authors.lastname: Schredelseker
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Kui
authors.initials: K
authors.lastname: Lu
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States.
authors.forename: Shamim
authors.initials: S
authors.lastname: Naghdi
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Franklin
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Hannah Dg
authors.initials: HD
authors.lastname: Fiji
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Huanqi
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Billy
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Haruko
authors.initials: H
authors.lastname: Nakano
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Ehrlich
authors.affiliation: Brain Science Institute, Saitama University, Saitama, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nakai
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Adam Z
authors.initials: AZ
authors.lastname: Stieg
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
authors.forename: James K
authors.initials: JK
authors.lastname: Gimzewski
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakano
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, United States.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.affiliation: Department of Anesthesiology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States.
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Ohyun
authors.initials: O
authors.lastname: Kwon
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Jau-Nian
authors.initials: JN
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004622:Embryo, Mammalian / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D014741:Video Recording; D050996:Voltage-Dependent Anion Channel 2 / Q000737:chemistry / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000502:physiology*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D050996:Voltage-Dependent Anion Channel 2; D029961:Zebrafish Proteins; D002118:Calcium
keywords: VDAC; arrhythmia; calcium handling; cell biology; developmental biology; fibrillation; heart; human; mitochondria; mouse; stem cells; zebrafish