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Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity.

Hirohito Shimizu | Johann Schredelseker | Jie Huang | Kui Lu | Shamim Naghdi | Fei Lu | Sarah Franklin | Hannah Dg Fiji | Kevin Wang | Huanqi Zhu | Cheng Tian | Billy Lin | Haruko Nakano | Amy Ehrlich | Junichi Nakai | Adam Z Stieg | James K Gimzewski | Atsushi Nakano | Joshua I Goldhaber | Thomas M Vondriska | György Hajnóczky | Ohyun Kwon | Jau-Nian Chen
eLife | 2015

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.

Pubmed ID: 25588501

Research resources used in this publication

None found

Antibodies used in this publication

None found

Associated grants

  • Agency: NHLBI NIH HHS, United States
    Id: HL107674
  • Agency: NIGMS NIH HHS, United States
    Id: GM071779
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL048509
  • Agency: NIGMS NIH HHS, United States
    Id: P41 GM081282
  • Agency: NIGMS NIH HHS, United States
    Id: P41GM081282
  • Agency: NHLBI NIH HHS, United States
    Id: R21 HL124503
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM059419
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL096980
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM071779
  • Agency: NHLBI NIH HHS, United States
    Id: HL081700
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL081700
  • Agency: NHLBI NIH HHS, United States
    Id: HL105699
  • Agency: NHLBI NIH HHS, United States
    Id: HL070828
  • Agency: NIGMS NIH HHS, United States
    Id: GM059419
  • Agency: NHLBI NIH HHS, United States
    Id: HL096980

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