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Elife. 2015 Jan 15;4. doi: 10.7554/eLife.04801.

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

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
2
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
3
MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States.
4
Department of Anesthesiology, University of California, Los Angeles, Los Angeles, United States.
5
Brain Science Institute, Saitama University, Saitama, Japan.
6
California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States.
7
Cedars-Sinai Heart Institute, Los Angeles, United States.

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.

KEYWORDS:

VDAC; arrhythmia; calcium handling; cell biology; developmental biology; fibrillation; heart; human; mitochondria; mouse; stem cells; zebrafish

PMID:
25588501
PMCID:
PMC4293673
DOI:
10.7554/eLife.04801
[Indexed for MEDLINE]
Free PMC Article

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