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

Authors

Hirohito Shimizu, University of California, Los Angeles
Johann Schredelseker, University of California, Los Angeles
Jie Huang, University of California, Los Angeles
Kui Lu, University of California, Los Angeles
Shamim Naghdi, Thomas Jefferson UniversityFollow
Fei Lu, University of California, Los Angeles
Sarah Franklin, University of California, Los Angeles
Hannah Dg Fiji, University of California, Los Angeles
Kevin Wang, University of California, Los Angeles
Huanqi Zhu, University of California, Los Angeles
Cheng Tian, University of California, Los Angeles
Billy Lin, University of California, Los Angeles
Haruko Nakano, University of California, Los Angeles
Amy Ehrlich, Thomas Jefferson University
Junichi Nakai, University of California, Los Angeles
Adam Z Stieg, University of California, Los Angeles
James K Gimzewski, University of California, Los Angeles
Atsushi Nakano, University of California, Los Angeles
Joshua I. Goldhaber, Cedars-Sinai Heart Institute
Thomas M. Vondriska, University of California, Los Angeles
György Hajnóczky, Thomas Jefferson UniversityFollow
Ohyun Kwon, University of California, Los Angeles
Jau-Nian Chen, University of California, Los Angeles

Document Type

Article

Publication Date

1-15-2015

Comments

This article has been peer reviewed. It is the author’s final published version in eLife

Volume 4, January 2015

The published version is available at DOI: 10.7554/eLife.04801 Copyright © Shimizu et al.

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.

Recommended Citation

Shimizu, Hirohito; Schredelseker, Johann; Huang, Jie; Lu, Kui; Naghdi, Shamim; Lu, Fei; Franklin, Sarah; Fiji, Hannah Dg; Wang, Kevin; Zhu, Huanqi; Tian, Cheng; Lin, Billy; Nakano, Haruko; Ehrlich, Amy; Nakai, Junichi; Stieg, Adam Z; Gimzewski, James K; Nakano, Atsushi; Goldhaber, Joshua I.; Vondriska, Thomas M.; Hajnóczky, György; Kwon, Ohyun; and Chen, Jau-Nian, "Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity." (2015). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 212.
https://jdc.jefferson.edu/pacbfp/212

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

25588501